Medical fluid transfer and injection apparatus and method

ABSTRACT

Drug delivery system, injection device, transfer apparatus, vial holder and method of administering and transferring are disclosed which provide for passive warming of chilled injectable transferred through the transfer apparatus and into the injection device. The injection device may include a skin-facing surface including a skin boundary displacement extension or structure around a needle injection site to create a high pressure zone in the tissue. Radio frequency tracking and monitoring features for tracking patient compliance also may be provided.

The present application is a continuation-in-part of InternationalApplication No. PCT/US15/53539, filed Oct. 1, 2015, which claims thebenefit of Unites States Provisional Patent Application Ser. No.62/059,476, filed Oct. 3, 2014. The present application also claimspriority to and the benefit of U.S. Provisional Patent Application Ser.No. 62/314,729, filed Mar. 29, 2016, and U.S. Provisional PatentApplication Ser. No. 62/315,762, filed Mar. 31, 2016. This applicationhereby incorporates by reference the entire specification, drawings andclaims of each of the above applications as if they have been fullyrepeated herein.

The present subject matter generally relates to devices and methods foradministering the contents of vials and more specifically to adisposable one-time use apparatus and method that transfers and mixesthe contents of one or more vials into a disposable injection device foradministration into a subject such as a human being.

BACKGROUND

Vials are one of the preferred container closure systems used by thepharmaceutical industry due to their extensive clinical history andrecord of long term stability with a wide variety of drugs.Pharmaceutical drugs including biologics standard containers such asvials. Additionally the industry has made a significant investment incapital equipment for aseptic vial filling. However, vials require thetransfer of the contained drug from the vial to an injection device fordelivery to the patient. New container closure systems such as prefilledsyringes and cartridges have been introduced that allow direct transferof the drug from the syringe or cartridge to the patient. Injectiondevices such as autoinjection devices and pens have been developed toutilize these newer forms of container closure. Because of uncertaintyabout long-term drug stability, and the extensive manufacturingresources already in place, devices that incorporate standard containerclosure systems such as vials, prefilled syringes or cartridges aregreatly preferred by the pharmaceutical industry over devices thatrequire a custom form of drug containment.

However, vials, prefilled syringes and cartridges are not necessarilythe optimum containers for a drug delivery device. This is especiallytrue in the case of delivery devices that deliver relatively highvolumes of drugs (2-50 cc) or high viscosity (over 15 cP and up to about100 cP). Vials, prefilled syringes and cartridges are almost exclusivelycylinders made of glass, which imposes design constraints on forces andgeometries. Typical syringes and autoinjection devices are limited onthe viscosities of drug that can be delivered as well as by the forcesthat can be applied to the glass container closure systems. Newinjection devices have been developed including pumps for the deliveryof insulin that use custom container closures, but these systems arevery expensive, cannot generate high forces or pressures and typicallyreusable and/or refillable.

Due to factors including stability and time to market, pharmaceuticaldrugs including biologics are often initially marketed in a lyophilizedor powder form or in concentrated liquid form. Such drugs packaged invials in both liquid and powder formulations can require significantpreparation prior to administration. To facilitate the administration ofliquid formulations in vials, drugs in vials are often packaged with anempty syringe and multiple needles for aspiration out of the vials andinjection into the patient. In the case of powder formulations, anadditional diluent or solution vial may be provided to allow forreconstituting the powder drug into solution available for injection.

The risks associated with the preparation and administration of thesedrug forms are significant. They include the potential for needle stickinjury during the reconstitution and administration process as well aserrors with improper mixing and inaccurate dose volume or concentrationdelivered. This presents a real challenge for both trained caregiversand patients preparing and receiving the medication. Similar issues ofrisk can also apply to the transfer of ready-to-inject drug that must betransferred from a vial to an injection device.

This transfer also involves removal of the drug from the vial,measurement of the proper dose, and injection into the patient using asyringe. Incomplete transfer of the full volume of the vial necessitatesoverfilling of the vial by some 25-30% and the associated waste.Contamination of the drug with non-sterile ambient air that is injectedinto the vial, or improper sterile technique can cause contamination ofthe injectable drug.

On body injection devices have, in particular, been the subject ofcontinuing development in efforts to develop injection devices andmethods that offer benefits such as greater comfort and less pain whileproviding effective subcutaneous injection.

Accordingly, there continues to exist a need for new and/or improvedapparatus and methods for transfer, mixing and injection of medicamentdrugs from a source vial or vials to and into a subject.

DESCRIPTION

The description below is for purposes of illustration only and notlimitation. The present subject matter may be employed in a variety ofapparatus, systems and methods not depicted below.

SUMMARY

The present subject matter is directed, in part, to disposable,one-time-use apparatus, preferably on-body, and methods for preferablyautomatically mixing and/or transferring, upon user initiation, theinjectable contents of one or more standard vials or syringes into aninjection device and preferably simultaneously pressurizing theinjection device for subsequent automated injection into a subject andmethods for injecting medicament into a subject. The contents of thevial(s) may be any suitable injectable. For purposes of this descriptionand claims, the terms medicament, drug, injectable, fluid, medicine,medication, medical, fluid and the like are used comprehensively andinclude without limitation drugs of any type, therapeutic or diagnostic,antibiotics, biologics, sedatives, sterile water and other injectablematerials, either alone or in combination with one or more otherinjectables, and whether or not requiring reconstitution orconcentration adjustment or other processing before injection.

The present subject matter includes a transfer device and/or aninjection device of any suitable detailed construction, but transfer andinjection devices that are particularly useful in combination with theapparatus here are described in U.S. patent application Ser. No.61/326,492 filed Apr. 21, 2010; U.S. patent application Ser. No.13/637,756, filed Sep. 27, 2012; and U.S. patent application No.61/704,922, filed Sep. 24, 2012, all of which are hereby incorporated byreference herein.

In one aspect, a drug delivery system for the transfer andadministration of an injectable liquid drug into a subject. The systemincludes a transfer apparatus including an injection device dockingstation, an injectable inlet for receiving a chilled injectable having atemperature in range of about 2° C.-about 8° C., a fluid passagewaycommunicating between the injectable inlet and the injection devicedocking station. The system also includes an injection device comprisingan expandable chamber including an inlet that is configured forplacement into fluid communication with the transfer apparatus fluidpassageway when the injection device is received in the injection devicedocking station. The transfer and injection device are configured suchthat when at ambient temperature of about 15° C.-about 32° C., thetemperature of a single dose of chilled injectable that is transferredthrough the transfer apparatus into the injection device is passivelyincreased by at least about 5° C.-about 25° C.

In another aspect of the present subject matter, a drug delivery systemis provided for the transfer and administration of an injectable liquiddrug into a subject, comprising a transfer apparatus and an injectiondevice. The transfer apparatus includes an injection device dockingstation, an injectable inlet for receiving a chilled injectable having atemperature in range of about 2° C.-about 8° C., and a fluid passagewaycommunicating between the injectable inlet and the injection devicedocking station. The injection device comprises an expandable chamberincluding an inlet that is configured for placement into fluidcommunication with the transfer apparatus fluid passageway when theinjection device is received in the injection device docking station.The transfer and injection device are configured such that when atambient temperature of about 15° C.-about 32° C., the temperature of asingle dose of chilled injectable that is transferred through thetransfer apparatus into the injection device is passively increased byat least about 5° C.-about 25° C. No battery or other electrical heatingsource is needed, and this warming occurs within a relatively limitedamounted of time, particularly relative to the amount of time typicallyrequired for the usual technique of unaided warming—in others words,putting the chilled drug on the counter until it warms up. Variousadditional features of this aspect are set forth more fully below and inthe claims.

In a related aspect, a method of warming a flowable injectable suitablefor injection into a living subject is also provided. The methodcomprises flowing an injectable dose having an initial temperature inthe range of about 2° C.-about 8° C. through a passageway in a transferapparatus and into an injection device, the transfer apparatus andinjection apparatus being substantially at ambient temperature. Thetransfer apparatus and injection device are configured to passivelyraise the temperature of the injectable during flow through the transferapparatus and into the injection apparatus by about 5° C.-about 25° C.Various additional features of this aspect are also set forth more fullybelow and in the claims.

In accordance with another aspect, to enhance monitoring of patientcompliance, a drug injection device of the type including a housingcontaining an injectable reservoir and an injection needle is providedwith radiofrequency tag containing data identifying such device. The tagmay be an active tag or chip that signals compliance-related informationsuch as activation of the injection device and/or completion of aninjection. The following more detailed description and the claims setforth various additional features of this aspect.

In yet another aspect, a transfer apparatus for transferring aninjectable from a syringe containing such injectable to an injectiondevice, the transfer apparatus including a syringe docking station, aninjection device docking station and a fluid passageway extendingbetween a port associated with the syringe docking station and a portassociated with the injection device docking station. Similarly, thefollowing more detailed description and the claims also set forthvarious additional features of this aspect.

In another aspect, a medication injection device includes a housinghaving skin-facing surface that includes an injection needle aperturethrough which an injection needle may extend from the housing and a skindisplacement structure extending from the skin facing surface around theneedle aperture. The displacement structure serves to compress tissuearound the injection aperture and thereby creates a tissue pressure zonearound the injection aperture having higher pressure than in tissueoutwardly of the tissue pressure zone.

In yet another aspect, the medication injection device may include aninjection needle that is extendable through the aperture sufficiently toextend not more than about 5 mm into tissue when the skin-facing surfaceis placed in contact with tissue of a subject.

In yet another aspect, the medication injection device may include aninjection needle that is extendable through the needle aperturesufficiently to extend a selected subcutaneous distance into tissue, theselected distance providing substantially similar medication bolus depthas an injection needle extending substantially twice the selected depthin the absence of a tissue displacement structure.

In yet another aspect, the medication injection device may include aninjection needle extends to a subcutaneous depth of about 5 mm andgenerates a medication bolus depth of about 0.4 cm-about 0.45 cm.

In yet another aspect, the medication injection device may include aninjection needle movable from an initial retracted position to aninjection position, extending to a selected subcutaneous depth forinjection, and back to a final retracted position after injectioncomplete, the device being configured to maintain the tissue pressurezone after the needle returns to the retracted position.

In yet another aspect, the subject matter of this application may alsoinclude a method of medicament injection employing any of the injectiondevices set forth above.

In another aspect, a medicament delivery system for the transfer andadministration of an injectable liquid drug into a subject includes atransfer apparatus and an injection device, where the transfer apparatusincludes an injection device docking station. A wireless signal sendingunit is carried by the transfer apparatus and/or the injection device.

In yet another aspect, the present subject matter, as explained morefully below, is directed to systems and methods for monitoring patientcompliance.

In accordance with another aspect, to enhance monitoring of patientcompliance, a drug injection device of the type including a housingcontaining an injectable reservoir and an injection needle is providedwith radiofrequency tag containing data identifying such device. The tagmay be an active tag or chip that signals compliance-related informationsuch as activation of the injection device and/or completion of aninjection. The following more detailed description and the claims setforth various additional features of this aspect.

In accordance with another aspect, a medicament delivery system for thetransfer and administration of an injectable liquid drug into a subjectmay comprise a transfer apparatus and an injection device; the transferapparatus including an injection device docking station; and a wirelesssignal sending unit carried by the transfer apparatus and/or theinjection device.

In yet another aspect, the delivery system sending unit may comprise aradiofrequency tag containing data identifying such system. Theradiofrequency tag may be an active radiofrequency tag configured tosignal activation of the injection device. The active radiofrequency tagmay also be configured to signal completion of injection by theinjection device. Further, the active radiofrequency tag may beconfigured to transmit to signal activation of the injection device andto cease transmitting to signal completion of injection by the injectiondevice.

In yet another aspect, the delivery system includes a patient module andincludes an active radiofrequency tag configured to transmit a signalcontaining at least injection device information to a patient moduleremote from the injection device for receiving such signal and forstoring data associated with injection device and use thereof.

In yet another aspect, the patient module may be configured to transmitto a remote computer or network, information regarding the injectiondevice and use thereof together with unique patient information.

In yet another aspect, a medicament injection device may comprise ahousing containing an injectable reservoir and an injection needle, thedevice further comprising a wireless signal sending unit. The sendingunit may include an active radiofrequency tag configured to signalactivation of the injection device. The active radiofrequency tag may beconfigured to signal completion of injection by the injection device.Further, the active radiofrequency tag may be configured to transmit tosignal activation of the injection device and to cease transmitting tosignal completion of injection by the injection device.

In yet another aspect, the above device may include a patient modulethat may be remotely located, and the device sending unit or activeradiofrequency tag is configured to transmit a signal containing atleast injection device information to the patient module, the patientmodule being configured to receive such signal and store data associatedwith injection device and use thereof. The patient module may beconfigured to transmit to a remote computer or network, informationregarding the injection device and use thereof together with uniquepatient information.

In yet another aspect, the medicament delivery system or device mayinclude a sending unit that employs Bluetooth wireless technology.

In yet another aspect, the medicament delivery system and/or device mayinclude a sending unit configured for removal from the device fordisposal.

In yet another aspect, the medicament delivery system and/or may includea sending unit configured for removal to allow most of the deliverydevice to be recycled. The sending unit may be configured for removalfrom the transfer apparatus and/or injection device, and configured forremoval from the transfer apparatus and/or injection device to allowmost of the apparatus and/or device to be recycled.

Turning now to a more detailed description of the subject matter of theapplication and its various aspects and features, reference is firstmade to the accompanying drawings as briefly identified below.

BRIEF DESCRIPTION OF DRAWINGS

Examples of the subject matter of this patent application are shown forpurposes of illustration only, and not limitation, in the attacheddrawings, of which:

FIG. 1 is a perspective view of a single-vial system including thesingle vial holder, transfer apparatus and injection device systemembodying the present subject matter.

FIG. 2 is a perspective view of a dual vial system including the dualvial holder, transfer apparatus and injection device system embodyingthe present subject matter.

FIG. 3 includes a perspective view of a single vial holder with theremovable top included, a cross-section of the single vial holder withremovable top included and a perspective view of the single vial holderwith the removable top and vial cap removed.

FIG. 4 includes a perspective view with removable top included and across-section of the dual vial holder with removable top and vial capsremoved.

FIG. 5 is a cross-section of FIG. 2 in the area of the vial holdershowing the position of the vial access members relative to the septumsof the vials.

FIG. 6 is a cross-section of FIG. 1 in the area of the vial holdershowing the vial access member pierced through the septum of the vial.

FIG. 7 is a perspective view of the transfer apparatus shown in FIG. 1showing the vial holder and injection device receiving areas.

FIG. 8 is a close up of FIG. 5 illustrating the vial access memberpiercing the septum of the vial with the collapsible vial access membershield.

FIG. 9 is a schematic of the dual vial transfer system in FIG. 2 with afirst vial, a second vial, a transfer apparatus with a first and secondvariable pressure chambers and injection device including the fluidpathways.

FIG. 10 is a cross-section of FIG. 2 in a pre-fire position.

FIG. 11 is a schematic of the single vial transfer system in FIG. 1 witha drug vial, a transfer apparatus with a first variable pressure chamberand injection device including the fluid pathways.

FIG. 12 is a cross-section of FIG. 1.

FIG. 13 is a schematic of an alternative embodiment for the dual vialtransfer system in FIG. 2 with a first vial, a second vial, a transferapparatus with a first pressure chamber and injection device includingthe fluid pathways.

FIG. 14 is a schematic of an alternative embodiment of the dual vialtransfer system in FIG. 2 with a first vial, a second vial, a transferapparatus with a first and second variable pressure chamber andinjection device including the fluid pathways.

FIG. 15 is a schematic of an alternative embodiment of the dual vialtransfer system in FIG. 2 with a first vial, a second vial, a transferapparatus with a first pressure chamber, a dual lumen connector andinjection device including the fluid pathways.

FIG. 16 is a cross-section of FIG. 1.

FIG. 17 is a schematic of an alternative embodiment of the single vialtransfer system in FIG. 1 with a drug vial, a transfer apparatus with afirst variable pressure chamber, an injection device including the fluidpathways with check valves and flow restrictors.

FIG. 18 is a cross-section of FIG. 2.

FIG. 19 is a cross-section of FIG. 2.

FIG. 20 is a perspective view of the injection device.

FIG. 21 is a top view of a filled injection device showing the deliveryindicator in a full state.

FIG. 22 is top view of a filled injection device showing the deliveryindicator in an empty state.

FIG. 23 is a perspective view showing the underside of the injectiondevice with attached tape and fill port.

FIG. 24 is a perspective view showing the underside of the injectiondevice with tape detached and the fill and dispense ports exposed.

FIG. 25 is a cross-section of the injection device on the transferapparatus.

FIG. 26 is a perspective view of the injection device attached to theskin with the safety device installed.

FIG. 27 is a perspective view of the injection device attached to theskin with the safety device removed and the button up in a pre-firestate.

FIG. 28 is a perspective view of the injection device attached to theskin with the safety device removed and the button down in a firedstate.

FIG. 29 is a cross-section view of the injection device attached to theskin with the button up in a pre-fire state.

FIG. 30 is a cross-section view of the injection device attached to theskin with button down in a first fired state.

FIG. 31 is a cross-section view of the injection device attached to theskin with button down in a dispense state.

FIG. 32 is a cross-section view of the injection device attached to theskin showing the end of delivery indicator not triggered.

FIG. 33 is a cross-section view of the injection device attached to theskin showing the end of delivery indicator triggered.

FIG. 34 is a cross-section view of the injection device attached to theskin with button locked up in a post-fired state.

FIG. 35 is a perspective view of the injection device removed from theskin with the bandage remaining on the skin.

FIG. 36 is a perspective view of the injection device with the tophousing removed in a filled state.

FIG. 37 is a top view of the injection device shown in FIG. 36.

FIG. 38 is a perspective view of the injection device with the tophousing removed in an empty state.

FIG. 39 is a top view of the injection device shown in FIG. 38.

FIG. 40 is a perspective view of the single vial system in thepackaging.

FIG. 41 is a perspective view of the single vial system in the packagingopen.

FIG. 42 is a perspective view of the single vial system in the packagingwith the lid removed exposing the contents of the package.

FIG. 43 is a perspective view of the single vial system with the vialholder removed from the package and the vial cap removed.

FIG. 44 is a perspective view of the single vial system with the vialholder fully inserted into the transfer apparatus.

FIG. 45 is a perspective view of a dual vial system showing the vialholder installed.

FIG. 46 is a top view of FIG. 45 showing the volume controller in apreset state.

FIG. 47 is a top view of FIG. 45 showing the volume controller in a setstate.

FIG. 48 is a perspective view of a dual vial system with the volumecontroller removed and the vial holder depressed into the transferapparatus to start the mixing and transfer process.

FIG. 49 is a perspective view of a dual vial system after completion ofthe mixing and transfer process, filling of the injection device andrelease of the injection device removal interlock.

FIG. 50 is a perspective view of the single vial system with theinjection device filled and removed from the package.

FIG. 51 is a perspective view of the injection device placed on the skinand the safety in place.

FIG. 52 is a perspective view of the injection device placed on the skinand the safety removed.

FIG. 53 is a perspective view of the injection device placed on the skinand the button depressed to fire start the injection.

FIG. 54 is a perspective view of the injection device removed from theskin after the injection with the button in a locked up position and abandage remaining on the skin.

FIG. 55 is a perspective view of injection device embodying the presentsubject matter.

FIG. 56 is a cross-section of FIG. 55 showing the injection device withthe button in the first position.

FIG. 57 is an illustration (Van Gerwen, D. J. Needle-Tissue Interactionby Experiment. Ph.D. Thesis, Delft University of Technology, 2013. ISBN978-94-6186-238-9, pg. 11) showing four stages of needle penetrationinto tissue including a.) no contact, b.) boundary displacement, c.) tipinsertion and d.) shaft insertion.

FIG. 58 is a cross-section of FIG. 55 showing an injection device withthe button in a second position or dispense position.

FIG. 59 is a perspective view of a single vial transfer system with thedrug vial and injection device installed embodying the present subjectmatter.

FIG. 60 is a cross-section of FIG. 59 with depicting an aspect of thevial holder area showing the drug vial, a vial access member and anextension member in the down position.

FIG. 61 is a cross-section of FIG. 59 depicting an aspect of the vialholder area showing the drug vial, a vial access member and an extensionmember in the up position.

FIG. 62 is a cross-section of FIG. 59 with the box and tray removed anddepicting an aspect of the pressure chamber and fluid passageways.

FIG. 63 is a cross-section of FIG. 59 depicting an aspect of the vialholder area showing the drug vial, the vial access member and outletopening.

FIG. 64 is a cross-section of a single-vial system including the singlevial holder, transfer apparatus and injection device system.

FIG. 65 is a schematic of an alternative embodiment of the single vialtransfer system in FIG. 64 with a drug vial, a transfer apparatus with afirst variable pressure chamber, an injection device including the fluidpathways with check valves and flow restrictors.

FIG. 66 is a cross-section of FIG. 55 showing adhesive/device andadhesive/skin interfaces.

FIG. 67 is a perspective view of the bottom of an injection deviceshowing the different zones of the adhesive.

FIG. 68 is a cross-section of FIG. 55 showing bulging tissue on a devicewith permanently attached adhesive.

FIG. 69 is a cross-section of FIG. 55 showing bulging tissue on a devicewith multi-zone attached adhesive.

FIG. 70 is a perspective view of the top of an alternative injectiondevice.

FIG. 71 is a cross-section of FIG. 70 showing a dislodgment sensornon-engaged and the needle locked in the dispense position.

FIG. 72 is a cross-section of FIG. 70 showing a dislodgment sensorengaged and the needle and button retracted to post-fire position.

FIG. 73 is a cross-section of FIG. 55 showing an injection device withthe button in the first position or pause position.

FIG. 74 is a cross-section of FIG. 55 showing an injection device withthe button in a second position or dispense position.

FIG. 75 is a cross-section of FIG. 55 showing an injection device withthe needle retracted and the button in the up or pre-fire position.

FIG. 76 is a cross-section of FIG. 55 showing an injection device withthe button in a second position or dispense position.

FIG. 77 is a perspective view of a single vial transfer apparatus.

FIG. 78 is a perspective view of an injection device.

FIG. 79 is a cross-section of FIG. 78 showing an injection device withthe button in a second position or dispense position.

FIG. 80 is a schematic of an alternative embodiment of the single vialtransfer system in FIG. 64 with a drug vial, a transfer apparatus with afirst variable pressure chamber, an injection device including the fluidpathways with check valves and flow restrictors.

FIG. 81 is a cross-section of FIG. 77 depicting an aspect of the vialreceiving area.

FIG. 82 is a schematic of a dual vial transfer system with a first vial,a second vial, a transfer apparatus with a first and second variablepressure chambers and injection device including the fluid pathways.

FIG. 83 is a perspective view of an injection device with the attachedsafety sleeve.

FIG. 84 is a cross-section of FIG. 55 showing an injection device withthe button in second position or dispense position.

FIG. 85 is a cross-section of FIG. 59 depicting an aspect of the vialholder area showing the drug vial, vial access member and angle sensorin the open position.

FIG. 86 is a cross-section of FIG. 59 depicting an aspect of the vialholder area showing the drug vial, vial access member and angle sensorin the closed position.

FIG. 87 is a schematic of an alternative embodiment of the single vialtransfer system with a drug vial, a transfer apparatus with a firstvariable pressure chamber and an injection device including the fluidpathways with check valves.

FIG. 88 is a perspective view of a transfer device, with an associatedinjection device, embodying the present subject matter for use intransferring the contents of a syringe, also shown, into the injectiondevice.

FIG. 89 is a vertical cross-sectional view take through the transfer andinjection device with the syringe located in a docking station on thetransfer device.

FIG. 90 is a vertical cross-sectional view take through the transfer andinjection device with the syringe located in a docking station on thetransfer device, with the plane of the cross sectional at a differentposition than in FIG. 89.

FIG. 91 is a perspective view of the top or exposed side of a transferdevice and associated injection device for transferring the contents ofa pre-filled vial, such as was shown in earlier figures.

FIG. 92 is a perspective view of the underside of the transfer device ofFIG. 91, illustrating some of the fluid contacting surfaces and flowpaths that can contact the injectable during transfer and contribute toelevating the temperature of a chilled injectable.

FIG. 93 is a horizontal cross sectional view of the transfer device ofFIG. 92 illustrating some of the fluid passageways through which aninjectable moves during transfer to an injection device and associatedpassageway surfaces that contact the injectable and contribute toconductive heat transfer.

FIG. 94 is a perspective view of an injection device including an Rf tagand a tag reader or interrogator.

FIG. 95 is similar to FIG. 94, but shows the injection device in crosssection.

FIG. 96 is a perspective view of a transfer apparatus for transferringan injectable from a prefilled source, such as a vial, to an associatedinjection device in combination with an Rf reader.

FIG. 97 is a cross-sectional view of the transfer apparatus andinjection device of FIG. 96.

FIG. 98 is an enlarged view of a portion of the cross-section of FIG. 97viewed from a different angle.

FIG. 99 is a block diagram/flow chart, illustrating a system employingthe present subject matter for monitoring patient compliance.

FIG. 100 is a graph illustrating chilled drug warming employing one ofthe transfer and injection devices disclosed herein.

FIG. 101 is another graph illustrating chilled drug warming employinganother of the transfer and injection devices of the presentapplication.

FIG. 102 is yet another graph illustrating chilled drug warmingemploying another of the transfer and injection devices of the presentapplication.

FIG. 103 is an ultrasound image showing the subcutaneous depth of abolus injection employing a commercial infusion pump with a 9 mmsubcutaneous needle depth.

FIG. 104 is an ultrasound image showing the depth of a bolus injectionemploying injection device 7, similar to FIG. 56, with a 5 mm needledepth.

FIG. 105 depicts a compliance monitoring system.

FIG. 106 further depicts a compliance monitoring system.

FIG. 107 shows additional aspects of a compliance monitoring with aninjection device of the type described herein.

FIG. 108 shows yet further aspects of a compliance monitoring system inconnection with a cross-sectional view of an injection device asdescribed herein.

FIG. 109 Illustrates compliance monitoring with an injection device asdescribed herein with cross-sectional views illustrating the compliancestatus in different stages of injection device usage.

DETAILED DESCRIPTION

Referring to FIGS. 1 and 2, as set forth in more detail below, thedisposable, one-time use, single vial transfer and injection system 1shown in FIG. 1 may comprise a single vial holder 2, transfer apparatus3 and injection device 7. A disposable, one-time use, dual vial mixing,transfer and injection system 4 shown in FIG. 2 may comprise a dual vialholder 5, transfer apparatus 6 and injection device 7. As mentionedearlier, each of these aspects has separate utility and may be claimedseparately and/or in combination or sub-combination.

Referring to FIGS. 3 and 4, the single vial holder 2 shown includes ahousing 8 that includes a side wall 9, end wall 10 and apertures orviewing windows 11. Alternatively the vial holder 2 material may betransparent to allow for visualization of the contents of the vial 12.The housing 8 is shaped to define at least one or two or morevial-receiving cavities 13 or zones for securely holding a vial 12 ineach zone 13 as shown in FIG. 4. The cavities 13 in the vial holder 5may be sized for receiving standard injectable vial 12 of differentsizes such as from 1 to 30 ml. The vial 12 may be of the same size ordifferent sizes and may contain any desired injectable 14. In the dualvial holder 5 illustrated in FIG. 4, the vials may include one vial ofpowdered, lyophilized or liquid drug 15 and one vial of liquid ordiluent 16. The vial holder 5 may have the vials prepackaged andassembled therein by, for example, a drug manufacturer, or the vials maybe inserted into the vial holder 5 by the end user or by a medicalprofessional such as a pharmacist or nurse. The vial holder 5 may haveappropriate markings and/or features to only allow for the assembly ofcertain vials in certain cavities 13. For example, the powdered drugvial 15 may be inserted into a specific cavity 13 of the vial holder 5and diluent vial 16 in another cavity 13 of the vial holder 5. Theapertures or viewing windows 11 in the vial holder 5 allow for directvisualization of the contents 14 of the vials.

Referring to FIGS. 3 and 4, as a further alternative, the vial holder 5may be an assembly of individual vial holders 2, each of which holds asingle vial 12. For example, the injectable manufacturer may preassemblea vial 12 in an individual vial holder 2 which can then be joined withthe vial holder 2 of another vial 12, if needed, at the time ofinjection. For example, a drug manufacturer may provide a lyophilizeddrug 15 in its own vial holder 2 and the diluent 16, such as sterilewater or saline, in a separate vial holder 2. The user or medicalprofessional can then, as needed, join the individual vial holders 2 toform the vial holder assembly 5 for connection to the transfer apparatus6 shown in FIG. 2.

Referring back to FIG. 3, the vial holder 2 may include a removablecover 17 that normally covers and protects the end of the vial 18 duringshipping and storage. Typical standard commercial vials 12 include apierceable septum 19 located in the vial neck for accessing the vialcontents 14, which is covered by a removable vial cap or closure 20. Theremovable cover 17 may be configured to engage the vial cap 20 so thatremoval of the cover simultaneously removes vial cap 20 and exposes thevial septum 19 for accessing the contents 14 after any antisepticswabbing of the septum 19 that may be deemed necessary by the user. Thevial holder 2 may recess the vial 12 therein such that after the vialcap 20 is removed by the cover 17, the pierceable septums 19 arerecessed within the vial holder 2 to reduce the chance of contaminationby the user prior to insertion of the vial holder 2 into the transferapparatus 3 as shown in FIG. 1. This system is applicable to both singlevial holders 2 and dual vial holders 5.

Referring to FIG. 3, the vial holder 2 may include interlocks 27 toprevent the vial 12 from being removed once the vial 12 is inserted intothe vial holder 2. This helps prevent the vial 12 from falling out orbeing inadvertently removed during handling.

Referring to FIG. 5, the vial holder 5 may be assembled to the transferapparatus 6 with the vial caps removed and the vials 15, 16 installedinto the vial holder 5 by the device manufacturer. The exposed vialseptums 19 are held in close proximity to the vial access members 21, 52prior to activation. This configuration provides convenience byeliminating the need for the user to remove the vial caps, swab the vialtops 19 and assemble the vial holder 5 to the transfer apparatus 6 priorto use of the system 4.

Referring to FIG. 6, the vial holder 2 may be packaged separately fromthe transfer apparatus 3. In this case, the user would remove the vialcap with the removable cover 17, swab the vial top 19 (if necessary) andassemble the vial holder 2 into the transfer apparatus 3. As shown inFIG. 6, the vial holder 2 may include lock-out features 22 that interactwith the transfer apparatus 3 to prevent the vial holder 2 from beinginadvertently pulled out of the transfer apparatus 3 after activation bythe user.

Referring to FIG. 5, the vial holder 5 preferably is assembled to thetransfer apparatus 6 to configure the vials 15, 16 upside down in avertical position. This allows any liquid 23 in the vials to be indirect communication with the vial access members 21, 52 after insertionof the vial holder 5. This also forces the air 24 to the top of the vialin this orientation. To encourage the septums 19 to remainuncontaminated after removal of the vial caps and before insertion ofthe vial holder 5, the exposed vial septums 19 may be recessed into thevial holder 5 to prevent inadvertent contact as shown in FIG. 4. Thisconfiguration is applicable to single vial holder and dual vial holderconfigurations.

Referring to FIG. 6, the vial holder 2 preferably is mechanicallyconfigured with insertion features 25 in the transfer apparatus 3 toactuate like an on/off switch, i.e., to only have two states, open andclosed such as a light switch. This may prevent the user from pushingthe vial holder 2 into the transfer apparatus 3 half way and notallowing the vial access member 21 to pierce the septum 19 and allowcommunication between the contents 14 of the vial 12 and the transferapparatus 3. Additionally, the vial holder 2 may interface with aninterlock 26 in the transfer apparatus 3 to lock the vial holder 2 inthe closed position after full insertion of the vial holder 2 to preventthe vial holder 2 from being removed from the transfer apparatus 3 afterinsertion.

Referring to FIG. 7, the transfer apparatus 3 comprises an outer housing28 and defines a vial holder docking area or first receiving station 29and an injection device docking station or second receiving station 30(for removable injection devices). In the illustrated structure, thevial holder docking station 29 and injection device docking station 30are at opposite ends of the transfer apparatus housing 28.

Referring to FIG. 7, the transfer apparatus 3 may have an outer housing28 that is integrated into the packaging 31 of the system. The outerpackaging 31 may essentially form the bottom and side walls of thetransfer apparatus outer housing 28. All of the operational steps inusing the system up to the point of removal of the injection device mayoccur in this packaging 31. This may provide cost reduction and increaseease of use for the user. Additionally, incorporating the entiretransfer apparatus 3 into the packaging 31 eliminates the possible usererror that could occur if the user was required to remove the transferapparatus 3 from the package 31. The packaging 31 could include aplastic tub or tray that contains the system. Furthermore, the packaging31 could include everything within a shipping carton 32 that houses theentire system.

Referring to FIG. 7, the transfer apparatus 3 comprises a vial holderdocking area 29 that may include elongated a vial access member orpiercing member 21. This access member or piercing member 21 could beconfigured as pointed or blunt cannulas or needles. Referring to FIG. 8,the vial holder 5 with attached vial 12 is shown inserted into the vialdocking station 29 and the vial access member 21 piercing the vialseptum 19 allowing access to the contents 14 of the vial 12. The vialaccess member 21 may include a collapsible seal 33 to maintain sterilityof the vial access member 21 and fluid path prior to activation. Thecollapsible seal 33 may also attach and seal on the outside of the vial12 relative to the vial access member 21 to maintain sterility prior toactivation.

Referring to FIG. 8, the vial access member 21 of the transfer apparatus3 may comprise of multi-lumen tubes 34 to communicate with the internalfluid pathways 35 of the transfer apparatus 3. The vial access member 21preferably comprises one inlet tube 36 allowing air or fluid to enterthe vial 12 and one outlet tube 37 allowing for air or fluid to exit thevial 12. These inlet 36 and outlet 37 tubes may be separate and distinctand communicate with different fluid pathways in the transfer apparatus3. Because of the vertical orientation of the vial 12 in the upside-downposition, the lumen openings 38 in the vial access member 21 can beoriented so the inlet tube opening 36 is above the output tube opening37. This orientation allows for introduction of pressurized air orliquid through the upper inlet tube 36 and output of the vial contents14 through the lower output tube 37. Further, the outlet opening 37 maybe positioned near the bottom of the vial 12, adjacent to the septum 19to encourage the entire contents 14 of the vial 12 to enter the outletport 37 and be removed from the vial 12.

Referring to FIGS. 9 and 10, the transfer apparatus 6 is configured tocarry out all of the necessary steps to transfer and reconstitute (ifnecessary) injectable 14 contained within the vials 15,16 and transferthe mixture to the injection device 7 preferably automatically afteruser initiation of the process. The transfer apparatus 6 is configuredand preferably includes a propulsion system or systems, such aselectrically (e.g., battery powered) or mechanically (e.g., springloaded) actuated pumps, to direct diluent from the diluent vial 16 intothe injectable powder vial 15 and to direct the injectable 14 throughthe transfer apparatus 6 into the injection device 7.

Referring to FIGS. 9 and 10, the transfer apparatus 6 may also includean array of internal fluid pathways 35, as required to perform anytransfer, reconstitution, mixing, dilution or other processing of theinjectable 14 and transferring it from the vials 15, 16 in the vialholder 5 to the injection device 7. The fluid pathways 35 may includeflexible or rigid conduits or tubes. These fluid pathways 35 may alsoinclude check valves, filters, flow restrictors or other means 40 todirect the drug from the vials 15, 16 through transfer apparatus 6, intothe injection device 7.

Referring to FIGS. 9 and 10, the transfer apparatus 6 may includevariable volume pressure chambers or cylinders that have movablespring-loaded pistons therein and directly communicate with the internalfluid pathways 35. The chamber capacity for each variable volume chambermay be defined by chamber diameter and location of the piston within thechamber. The first pressure chamber 41 in transfer apparatus 6 maypreferably have an initial volume set by the manufacturer in the rangeof 1 to 30 milliliters. The initial contents of the first pressurechamber 41 may preferably include air 45. The piston 43 may be driven bya compression spring 44 in the first pressure chamber 41 whose volume isdefined and set by the manufacturer. The spring-loaded piston 43 may beof adequate size and configuration to produce 1 to 50 psi of static airpressure in the first pressure chamber 41. The volume of air 45 willdepend on the diameter of the chamber 41 and stroke position of thepiston 43 during operation. This pressure will depend on the relativevolume of air 45 displaced by the piston 43 and the force exerted by thespring 44. In other words, the force exerted by the spring 44 multipliedby the area of the piston 43 inside the chamber 41 will determine thestatic pressure within the chamber 41. The force exerted by the spring44 at its solid height or the beginning of the stroke may be much higherthan the force exerted by the spring 44 at end of its travel. The spring44 may be appropriately sized to control the rate at which air 45 isexpelled out of the pressure chamber 41 and thus the speed of the fluidtransfer in the transfer apparatus 6. The first pressure chamber 41 ispreferably configured to expel all of the air 45 out of the firstpressure chamber 41. Alternatively, a flow restrictor 55 in the outputpath 35 of the pressure chamber 41 could be used to control the rate atwhich air 45 is expelled out of the pressure chamber 41.

Referring to FIGS. 9 and 10, the chamber volume for the second pressurechamber 42 may be set by the manufacturer. Alternatively, the filledchamber volume for the second pressure chamber 42 may be set by the userat time of use using a dose selector or volume controller 48 in therange of 0.5 to 30 milliliters. The spring-loaded piston 46 in thesecond pressure chamber 42 may be of adequate size and configuration toproduce 1 to 200 psi of pressure in the second pressure chamber 42. Adose selector or volume controller 48 permits the user to select aprescribed dosage to be injected by the injection device 7 by settingthe filled volume of chamber 42. The dose selector 48 may be of anysuitable configuration. The dose selector 48 may be directly coupled tothe pressure plunger assembly chamber 93 which is moveable inside thepressure chamber 42. A trigger 49 within the pressure plunger assembly93 releases the piston 46 in the second pressure chamber 42 once thepiston has reached a position corresponding to the filled volumesetting. The user selects the desired dosage positions in the secondpressure chamber 42 by moving the dose selector 48 which positions thepressure chamber plunger assembly 93 to define a filled chamber volumeequal to the desired injection dosage. Alternatively, the position ofthe pressure plunger assembly 93 may already be set by the manufacturecorresponding to the delivery dose and the user operates the devicewithout making a dose adjustment.

Referring to FIGS. 9 and 10, the transfer apparatus 6 for a dual vialsystem 4 that provides for mixing and transfer includes a vial holder 5with a first vial 16 and second vial 15, a first variable volumepressure chamber 41, a second variable volume dose pressure chamber 42,fluid pathways 35, and check valves 40 to direct air from the firstpressure chamber 41 into the first vial 16 and the contents 23 of thefirst vial 16 into the second vial 15 and the resulting mixture 14 inthe second vial 15 into the second pressure chamber 42 which is thentransferred into the injection device 7.

Referring to FIG. 8, upon complete insertion of the vial holder 5 intothe transfer apparatus 6 and the subsequent introduction of the vialaccess members 21 through the septums 19 and into the vial chambers 12by the user allows for the release of the pressure chamber trigger 50shown in FIG. 10.

Referring to FIGS. 9 and 10, release of the trigger 50 then releases thefirst pressure chamber spring 44 allowing the advance of the firstpressure chamber piston 43 in the first pressure chamber 41 causing theair 45 in the first pressure chamber 41 to be forced through the inlettube 36 of the first vial access member 21 and into the first vial 16through internal passage ways 35 in the transfer apparatus 6. As moreair 45 is forced out of the first pressure chamber 41 and into the firstvial 16 through the inlet tube 36, the air 45 rises to the top of thefirst vial 16 due to its vertical orientation within the vial holder 5.The increasing air pressure in the first vial 16 causes the fluid 23 inthe vial 16 to be expelled through the outlet tube 37 of the first vialaccess member 21 and through the inlet tube 51 of the second vial accessmember 52. The fluid 23 from the first vial 16 entering the second vial15 mixes with the contents 54 of the second vial 15 containing theliquid or powdered drug and exits though the outlet tube 53 of thesecond vial access member 52 and into the second pressure chamber 42. Inthe same manner within the reconstitution configuration, the advancingplunger 43 in the first pressure chamber 41 continues to push a firstfluid 23 then air 45 mixture through the first vial 16 into the secondvial 15. The increasing air pressure in the top of the second vial 15causes the reconstituted mixture 14 in the bottom of the second vial 15to be expelled out into the second pressure chamber 42. A ‘popoff’ orcheck valve 40 or other type of valve may be present on the outlet tube53 of the second vial access member 52 to encourage all of the contents23 of the first vial 16 to enter the second vial 15 before the contents14 of the second vial 15 are expelled out into the second pressurechamber 42. The valve would not open until the pressure corresponding tothe plunger 43 pushing substantially all the air 45 out of the firstpressure chamber 41. This ensures that the contents 54 of the secondvial 15 may be thoroughly mixed with the contents 23 of the first vial16 before the mixture 14 exits the second vial 15 and into the secondpressure chamber 42. Alternatively, a flow restrictor 55 may be used inthe fluid pathway 35 to delay the transfer and increase the mixing time.

Referring to FIGS. 9 and 10, injectable drug 14 flows from the secondvial 15 after reconstitution, into the second pressure chamber 42,filling the chamber 42 to the extent permitted by the piston 46 positionas selected using the dose indicator 48 by the user or manufacturer,which corresponds to the desired dosage. When the desired volume of thesecond pressure chamber 42 has been achieved, the second pressurechamber trigger 49 releases the spring 47 and forces the piston 46forward, expelling the selected dosage of injectable drug 14 underpressure into the injection device 7. Calibration of the dose volumeshown on the dose selector 48 and the actual dose received by the usermay be required to account for fluid loss in the internal pathways 35 ofthe transfer apparatus 6. The injection device 7 is now full and readyto remove from the transfer apparatus 6.

Referring to FIGS. 11 and 12, an alternative transfer apparatus 3 withina single vial system 1 that does not perform mixing but only transfersfluid 14 from a single vial 15 to the injection device 7 is provided.This alternative transfer apparatus 3 includes a vial holder 2 withsingle vial 15, a variable volume pressure chamber 56, fluid pathways35, and check valves 40 to direct the contents 14 from the vial 15 intothe injection device 7. The inlet tube 36 of the vial access member 21is vented to the environment 57 to allow air 58 to enter the vial 1. Theoutlet tube 37 of the vial access member 21 is connected to the pressurechamber 56.

Referring to FIGS. 11 and 12, the full insertion of the vial holder 2into the transfer apparatus 3 by the user causes the introduction of thevial access member 21 through the septum 19 of the vial 15 to access thecontents 14 of the vial 15. This also triggers the release of thepressure chamber trigger 59. The pressure release trigger 59 releasesthe plunger 60 within the pressure chamber 56 connected to a withdrawspring 61. The withdraw spring 61 forces the plunger 60 to retract andwithdraw fluid 14 from the vial 15 and fill the pressure chamber 56. Aspecified amount of fluid 14 withdrawn by the chamber 56 could be set bythe manufacturer by limiting the retraction of the plunger 60.Additionally, the chamber 56 can be configured to withdraw all of thefluid 14 from the vial 15 by retracting the plunger 60 to its fulltravel. Once the plunger 60 reaches a set position within the pressurechamber 56, it interacts with a dispense trigger 62 that releases adispense spring 63 to force the liquid 14 out of the pressure chamber 56into the injection device 7. Check valves 40 could be employed toprevent fluid 14 from going back into the vial 15.

Referring to FIG. 13, an alternative transfer apparatus 6 for a dualvial system 4 that provides for mixing and transfer includes a vialholder 5 with a first vial 16 and second vial 15, a variable volumepressure chamber 56, fluid pathways 35, and check valves 40 to directthe contents 23 of the first vial 16 into the second vial 15 and theresulting mixture 14 into the pressure chamber 56. This mixture 14 isthen transferred back into the second vial 15 and then transferred intothe injection device 7. In this embodiment, the inlet tube 36 of thefirst vial access member 21 is vented to the environment 57 to allow air58 to enter the vial 16. The outlet tube 37 of the first vial accessmember 21 is connected to the inlet tube 51 of the second vial accessmember 52. The outlet tube 53 of the second vial access member 52 isconnected to the variable volume pressure chamber 56. A fluid pathway 35includes check valves 40 that are located between the first vial accessmember 21, the second vial access member 52 and the injection device 7.

Referring to FIG. 13, the full insertion of the vial holder 5 into thetransfer apparatus 6 by the user causes the introduction of the vialaccess members 21, 52 through the septums 19 of the vials 15, 16 toaccess the contents 23, 54 of each vial 15, 16. This also triggers therelease of the pressure chamber trigger. The pressure chamber triggerreleases the plunger 60 within the pressure chamber 56 connected to awithdraw spring. The withdraw spring forces the plunger 60 to retractand withdraw fluid 23 from the first vial 16 which fills the second vial15. This filling also results in mixing of the fluid 23 from the firstvial 16 and the contents 54 of the second vial 15. The resulting mixture14 from the second vial 15 fills the pressure chamber 56 until all ofthe fluid 23 is removed from the first vial 16. The rate at which thefirst vial 16 fills the second vial 15 can be controlled with checkvalves 40 or flow restrictors 55. The amount of fluid 23 withdrawn fromthe first vial 16 can be set in the chamber 56 by the manufacturer. Oncethe plunger 60 in the chamber 56 reaches a set position within thepressure chamber 56, it interacts with a dispense trigger that releasesa dispense spring to force the liquid 14 out of the pressure chamber 56back into the second vial 15. This has an advantage to allow foradditional mixing of the fluid 23 from the first vial 16 and thecontents 14 of the second vial 15. Once all of the fluid 14 from thechamber 56 is dispensed back to the second vial 15, the solution 14 istransferred to the injection device 7. The volume of the pressurechamber 56 could be set to be larger than the total fluid volume so thatadditional air 58 is drawn into chamber 56. This additional air 58 couldbe helpful in insuring that all of the liquid 14 is transferred into theinjection device 7 that may otherwise have resided in the fluid pathways35. Check valves 40 could be employed anywhere in the fluid pathways 35to prevent fluid 14 from going back into the first vial 16 duringtransfer of the mixture 14 from the second vial 15 to the injectiondevice 7. Flow restrictors 55 could be employed anywhere in the fluidpathway 35 to control the amount of mixing time of within the secondvial 15 before transfer of the mixture 14 to the injection device 7.

Referring to FIG. 14, an alternative transfer apparatus 6 for a dualvial system 4 that provides for mixing and transfer includes a vialholder 5 with a first vial 16 and second vial 15, a first variablevolume pressure chamber 56, a second variable volume pressure chamber42, fluid pathways 35, and check valves 40 to direct the contents 23 ofthe first vial 16 into the second vial 15 and the resulting mixture 14into the pressure chamber 56. This mixture 14 is then transferred fromthe first pressure chamber 56 to a second pressure chamber 42 and thentransferred into the injection device 7. In this embodiment, the inlettube 36 of the first vial access member 21 is vented to the environment57 to allow air 58 to enter the vial 16. The outlet tube 37 of the firstvial access member 21 is connected to the inlet tube 51 of the secondvial access member 52. The outlet tube 53 of the second vial accessmember 52 is connected to the first variable volume pressure chamber 56.A fluid pathway 35 include a check valve 40 also exists between thefirst vial access member 21, the second vial access member 52 and thesecond pressure chamber 42 and the injection device 7.

Referring to FIG. 14, the full insertion of the vial holder 5 into thetransfer apparatus 6 by the user causes the introduction of the vialaccess members 21, 52 through the septums 19 of the vials 15, 16 toaccess the contents 23, 54 of each vial 15, 16. This also triggers therelease of the pressure chamber trigger. The pressure chamber triggerreleases the plunger 60 within the pressure chamber 56 connected to awithdraw spring. The withdraw spring forces the plunger 60 to retractand withdraw fluid 23 from the first vial 16 which fills the second vial15. This filling also results in mixing of the fluid 23 from the firstvial 16 and the contents 54 of the second vial 15. The resulting mixture14 from the second vial 15 fills the pressure chamber 56 until all ofthe fluid 23 is removed from the first vial 16. The rate at which thefirst vial 16 fills the second vial 15 can be controlled with checkvalves 40 or flow restrictors 55. The amount of fluid 23 withdrawn fromthe first vial 16 can be set in the chamber 56 by the manufacturer. Oncethe plunger 60 in the chamber 56 reaches a set position within thepressure chamber 56, it interacts with a dispense trigger that releasesa dispense spring to force the liquid 14 out of the pressure chamber 56back into the second vial 15. Once all of the fluid 14 from the chamber56 is dispensed back to the second vial 15, the solution 14 istransferred into the second pressure chamber 42, filling the chamber 42to the extent permitted by the piston 46 position as selected using thedose indicator by the user or manufacturer, which corresponds to thedesired dosage. When the desired volume of the second pressure chamber42 has been achieved, the second pressure chamber trigger releases thesecond pressure chamber spring and forces the piston 46 forward,expelling the selected dosage of injectable drug 14 under pressure intothe injection device 7. Check valves 40 could be employed anywhere inthe fluid pathway 35 to prevent fluid 14 from going back into the firstvial 16 during transfer of the mixture 14 from the second vial 15 to thesecond pressure chamber 42 and to the injection device 7. Flowrestrictors 55 could be employed anywhere in the fluid pathway 35 tocontrol the amount of mixing time of within the second vial 15 beforetransfer of the mixture 14 to the second pressure chamber 42.

Referring to FIG. 15, an alternative transfer apparatus 6 for a dualvial system 4 that provides for mixing and transfer includes a vialholder 5 with a first vial 16 and second vial 15, a variable volumepressure chamber 56, a dual lumen connector 94, inlet fluid pathway 95,outlet fluid pathway 96 and check valves 40 to direct the contents 23 ofthe first vial 16 into the pressure chamber 56 through the inlet line 95during retraction of the plunger 60 within the pressure chamber 56. Theadvancement of the plunger 60 after full retraction within the pressurechamber 56 causes the fluid contents 23 to flow from the pressurechamber 56 into the second vial 15, mix with the contents 56 of thesecond vial 15 and the resulting mixture 14 flows into the injectiondevice 7. A check valve 40 in the outlet fluid pathway 96 would preventthe contents 56 of the second vial 15 from being pulled into thepressure chamber 56 during the retraction phase. A check valve 40 in theinlet fluid pathway 95 would prevent the fluid contents 23 in thepressure chamber 56 from being transferred back to the first vial 16during advancement of the plunger 60. A check valve in the fluid pathway35 from the second vial 15 and the injection device 7 prevents themixture from being transferred back from the injection device 7 to thesecond vial 15. Flow restrictions 55 could be employed anywhere in thefluid pathways 35, 95, 96 to control the rate of fluid transfer.Alternatively, the use of the dual lumen connector 94 could also be usedfor a single vial transfer system 1 in the same manner to remove andadvance fluid in different fluid pathways.

Referring to FIG. 16, the pressure chambers in the abovementionedembodiments may be configured with an outlet port 64 that is biased oroff-center compared to a normal syringe to take advantage of gravity.When the pressure chamber 59 is filled with liquid 14 during a transferprocess, there may be some air 58 that is introduced into the chamber 59in addition to liquid 14. During the process of expelling the liquid 14from the pressure chamber 59, it may be advantageous to control theorder of when air 58 or liquid 14 is expelled from the pressure chamber59. For example, if the outlet port 64 of the pressure chamber 59 isoriented down, during the process of expelling the liquid 14 from thepressure chamber 59, all of the liquid 14 is expelled first then theremaining air 58 is expelled last since the air bubble is oriented tothe top of the pressure chamber 59. Conversely, if the outlet port 64 isoriented up, during the process of expelling the liquid 14 from thepressure chamber 59, all of the air 58 is expelled first then theremaining liquid 14 last. This has particular advantage when usinghydrophobic or hydrophilic filters to remove unwanted air 58 from thelines during the transfer of liquid 14 to the injection device 7.

The transfer apparatus may employ a variety of devices or procedures toenhance mixing. For example, the transfer apparatus may inject thediluent into the drug-containing vial in a swirling manner to enhancemixing and/or may employ or introduce mixture-enhancing members such asdynamic or static mixers, e.g., mixing balls, augers or propellers,oscillating injection tubes, or the like. These techniques could beemployed within the second vial or one of the syringes. Additionally,the transfer apparatus may have an intermediate chamber between theoutlet tube of the second vial access member and the pressure chamber toallow for the abovementioned enhanced mixing techniques and procedures.The transfer apparatus also may be configured to move the injectablevial to induce turbulence and enhance mixing, such as by spinning theinjectable vial. A flow restrictor may be used in the air or drug pathto increase the transfer time to allow for greater mixing.

Referring to FIGS. 16 and 17, another optional feature of the transferapparatus 3 is a filter 65 in the injectable fluid pathway 35 forfiltering the injectable 14 to remove particulate before it isintroduced into the injection device 7. The filter 65 may be a membrane,depth filter or other suitable filtration media that is of sufficientlysmall pore size or effective pore size to remove objectionableparticulate, which may include but not be limited to undissolvedinjectable 14 in those situations where the injectable 14 isreconstituted by the transfer apparatus 3.

Referring to FIGS. 16 and 17, withdrawing injectable from the vial 15may require or be enhanced by the introduction of displacement air 58into the vial 15. In another aspect of the present subject matter, thetransfer apparatus 3 may include a displacement air pathway or vent 66that communicates with the interior of the vial(s) to allow displacementair 58 to enter the vial 15 as the injectable 14 is withdrawn. Aspreviously discussed, the vial access member 29 for piercing the vialseptum 19 may have inlet 36 and outlet 37 tubes, one for injectable 14flowing from the vial 15 and one for displacement air 58 flowing intothe vial 15. The displacement air 58 flow pathway 35 in the transferapparatus 3 may include a sterile filter 65 such as membrane or depthfilter 65 having an actual or effective pore size of about 0.22 micronsor smaller for filtering the displacement air 58. Such a pore size issufficiently small to prevent introduction of pathogens into the vial 15with the displacement air 58, reducing the risk of contamination of theinjectable 14.

Referring to FIGS. 16 and 17, the transfer apparatus 3 may include anair remover 67 in communication with injectable 14 fluid pathway 35leading from the vial 15 to the injection device 7. Such an air remover67 may include a bubble trap, air gap of other configuration in theinjectable 14 fluid pathway 35 that removes air 58 from the injectable14 fluid pathway 35 before it is introduced into the injection device 7.This air remover 67 may be configured with a hydrophobic filter 65 or acombination of hydrophobic 68 and hydrophilic 69 filters. A hydrophobicfilter 68 would allow for the venting of air from the transfer apparatus3 but not the passage of liquid 14. A hydrophilic filter 69 would allowthe passage of liquid 14 but not the passage of particulate or air 58.The combination and position of the filter 69 in the fluid pathway 35 ispreferable in removing all of the air 58 during the transfer process.

Referring to FIGS. 18 and 19, the transfer apparatus 6 may also haveadditional features as well as those described above. One such featureis an interlock 70 between the dose selector 48 and the vial dockingstation 29. This can be, for example, a mechanical interference member97 that prevents the user from loading vials into the docking station 29until a dosage has been selected. Mechanically, the dosage selector 48may be linked to an interference member 97 at the docking station 29which normally resides in a load-prevention position to preventsinsertion of the vial holder 5 into the vial holder station 29 unlessmoved to a load-permitting position when the dosage member 48 is movedto a dosage selected position. Of course, for administering injectablefrom a vial that contains a single dose of injectable or a single vial,all of which is to be injected, the transfer apparatus need not includea dose selection capability.

Referring to FIGS. 18 and 19, the transfer apparatus 6 may include aninterlock 71 between the transfer apparatus 6 and the injection device 7to prevent the injection device from being removed prior to filling andindicate when the injection device 7 is ready for removal from thetransfer apparatus 6. Mechanically, a locking pin 72 may be linked tothe injection device 7 to prevent removal prior to the injection device7 being completely filled by the transfer apparatus 6. The locking pin72 may be part of the transfer apparatus 6 and communicate with pistonin the pressure chamber 42. When the pressure chamber 42 has expelledall of the injectable 14, this may mechanically trigger the locking pin72 to move away from the injection device 7, allow for removal of theinjection device 7 from the transfer apparatus 6 by the user.

Referring to FIG. 18, the transfer apparatus 6 may include an interlockbetween the transfer apparatus 6 and the injection device 7 to controlhow the injection device 7 is removed from the transfer apparatus 6.Mechanically, a flange or other protrusion 73 on the injection device 7may mechanically interface with an undercut in the transfer apparatus 6.This configuration may allow for one-way rotation of the injectiondevice 7 relative to the transfer apparatus 6 for removal by the user.

Referring to FIGS. 18 and 19, the transfer apparatus 6 may include alocking feature that prevents the injection device 7 from beingactivated while docked on the transfer apparatus 6. For example, amechanical interference member such as a locking pin, arch or othermeans 72 could extend out of the transfer apparatus 6 and mechanicallylock the injection device 7 at the actuator or button in the upposition. Alternatively, the mechanical interference member 72 could bea shield that covers the entire injection device 7 to prevent access tothe injection device 7 while on the transfer apparatus 6. The arch orshield 72 may be part of the transfer apparatus 6 and communicate withthe pressure chamber 42. When the pressure chamber 42 has expelled allof the injectable 14 into the injection device 7, this may mechanicallytrigger the arch or shield 72 to unlock and move away from the injectiondevice 7. This allows access to the injection device 7 and removal fromthe transfer apparatus 6 by the user.

Another optional feature on the transfer apparatus is a quick releasefilling port or access member feature between the transfer apparatus andthe injection device to allow for the quick release of the injectiondevice from the transfer apparatus and to prevent the injection devicefrom being reattached to the transfer apparatus. After the injectiondevice is filled and ready to remove from the transfer apparatus, theuser may remove the injection device. The filling tube or access member83 of the transfer apparatus may be spring loaded such that when theinjection device is removed from the transfer apparatus, the fillingtube 83 springs down into the transfer apparatus. This allows for quickrelease of the tube 83 from the filling port 81 of the injection devicepreventing inadvertent leaking of the injection device at the fillingport 81. This also makes the filling tube 83 inaccessible to the user,thus preventing reattachment of the injection device onto the transferapparatus.

Referring to FIG. 18, the injection device 7 and transfer apparatus 6are preferably configured for removable attachment of the injectiondevice 7. In the current embodiment, after transfer of the injectablefluid 14 from the second pressure chamber 42 within the transferapparatus 6 into the injection device 7 and release of the interlock 71on the transfer apparatus 6, the injection device 7 is ready to beseparated from injection device docking station 30 of the transferapparatus 6 for application to the skin of a subject. As previouslymentioned, alternative embodiments described herein include the transferof the injectable fluid from a single pressure chamber directly to theinjection device.

Referring to FIG. 20, the injection device 7 may be of any suitableconfiguration. As explained earlier, the injection device mayadvantageously employ one or more of the features of the injectiondevices described in U.S. patent application Ser. No. 61/326,492 filedApr. 21, 2010; U.S. patent application Ser. No. 13/637,756, filed Sep.27, 2012; and U.S. patent application No. 61/704,922, filed Sep. 24,2012, which are all hereby incorporated by reference herein.

Referring to FIGS. 20-22, the injection device 7 has a generallylow-profile, disc shaped outer housing 74 with an upper surface 75 and alower surface 76, through which an injection needle or cannula protrudeswhen actuated by the user. The upper surface 75 has an actuator orbutton 77 to start the injection and a clear section 80 of the housing74 that allows the subject or medical professional to view theexpandable member 78 to ascertain the amount of injectable fluid 79 inthe device 7. For example, the user could determine whether theinjection has commenced or concluded. More preferably, the expandablemember 78 and/or the clear section 80 of the housing 74 may begraduated, such as by line markings 127 or the like, so that the patientor medical professional can visually determine the amount of injectablefluid 79 remaining with greater precision—such as, for example, about50% complete or about 75% complete. In addition, the expandable member78 may itself include or interact with a feature on the outer housing 74to show the amount of injectable fluid 79 remaining. For example, whenthe injection device 7 is full of drug 79, the clear section 80 may showone color such as but not limited to green. When the injection device 7is empty of drug 79, the clear section 80 may show a different colorsuch as but not limited to red. In the middle of dispense, the clearsection 80 could show a combination of colors.

Referring to FIGS. 23-25, the undersurface 76 of the injection device 7includes a filling port 81 and a dispense port 82. The filling port 81is the interface that allows the transfer apparatus filling tube 83 totransfer liquid 79 to the injection device 7. The dispense port 82 alsocontains an internal pathway 84 between the expelled injectable 79 fromthe expandable member 78 and the needle 85. The filling port 81 anddispense port 79 may be in direct fluid communication through internalpathways 86, or they may be combined into a single port.

Referring to FIGS. 23-25, the injection device may preferably include afilling port 81 that includes a check valve 87 to prevent pressurizedinjectable 79 from leaking out of the injection device 7 when theinjection device 7 is removed from the transfer apparatus 6 and thefilling port 81 is removed from the filling tube 83.

Referring to FIGS. 23-25, the injection device 7 may also have a fillingport 81 that is configured to accept the insertion of a syringe. Thissyringe may be configured with a luer fitting or a needle. This fillingport 81 configuration allows for the manual filling of the injectiondevice by the user. The transfer apparatus 6 may still be used but wouldnot be required in this configuration.

Referring to FIGS. 23-25, the injection device 7 may also have adispense port 82 that is configured to directly connect to anintravenous cannula via attached tubing or a standard needle port.

Referring to FIGS. 23-25, the undersurface 76 of the injection device 7carries an adhesive 88 for securing the injection device 7 temporarilyto the skin of a subject until the injection is complete. During removalof the injection device 7, an adhesive tape liner 89 may be removedautomatically exposing an adhesive surface 88 on the undersurface 76 ofthe injection device 7 that may be used to adhere the injection device 7to the patient's skin. Alternatively, the tape liner 89 may have a tab90 that the user pulls to manually remove before adhering the injectiondevice 7 to the skin. Alternatively this tab may be attached to thesurface of the transfer device 4 so that the tape liner is automaticallyremoved upon removal of the injection device 7.

Referring to FIGS. 23-25, the injection device 7 may have an adhesivetape flange 91 that extends beyond the undersurface base 76. This flange91 of adhesive tape 88 can act as a strain relief between the injectiondevice 7 and skin surface, reducing the risk of accidentally dislodgingthe injection device 7 from the skin. In other words, similar to atapered strain relief on a wire where it enters into a connector, theextended adhesive flange 91 acts to distribute the load on both sides ofthe connection point between the adhesive tape 88 and the undersurfacebase 76 of the injection device 7 to reduce any stress risers at theadhesive tape 88 and skin interface.

Referring to FIGS. 23-25, the injection device 7 may be configured witha tapered underside surface 98 that presses on the adhesive flange 91 tosecurely attach the adhesive tape 88 to the skin as the user is securingthe injection device 7 to the skin without additional user intervention.By using the compliance of a person's skin when pressing the injectiondevice 7 against the skin, the tapered underside surface 98 of theinjection device 7 effectively presses the flange 91 of the adhesivetape 88 against the skin but the upper exposed surface of the flange 91portion does not have exposed adhesive and therefore is not attached tothat portion of the tapered underside surface 98. The user is notrequired to run their finger around the flange 91 to secure theinjection device 7 to the skin making it a much simpler method ofadhesive tape 88 attachment.

Referring to FIGS. 23-25, the injection device 7 may have an undersidesurface 76 that is flexible or compliant in lieu of being rigid to allowfor improved attachment by conforming of the injection device 7 to theskin during application.

Referring to FIGS. 26-28, after the injection device 7 is placed againstor adhered to the skin 99, a safety mechanism or lock-out mechanism maybe automatically released and the injection device 7 is ready to fire(inject). In other words, the injection device 7 is prevented from beingactuated (it is locked out) until it is placed against the skin.Alternatively, the user may manually remove a safety 100 such as asafety pin, safety sleeve, or collar to release the injection device tobe ready to fire (inject). The injection device 7 preferably cannot befired until the safety mechanism 100 is released. The safety mechanism100 may be passive or active and manually triggered by the user orautomatically triggered by the injection device 7.

Referring to FIGS. 26-28, the injection device 7 may use an actuator orbutton 77 and a visual indicator 101 in combination to define the stateof the injection device 7 after it has been removed from the transferapparatus. For example, when the button 77 is in the up position and theindicator 101 has one color such as but not limited to green, this mayindicate that the injection device 7 is ready to start the injection.Additionally, the button 77 may have a side wall 102 that is a differentcolor from its top 103. When the button 77 is depressed, the user cannotsee the sidewall 102 of the button 77; this may indicate that theinjection device 7 is in use. The injection device 7 may alert the userwhen the injection of the drug is completed. This alert could be in theform of visual indicators, audible sounds, mechanical movements or acombination. The button 77 is ideally designed to give the user audible,visual and tactile feedback when the button 77 ‘pops up’ into thelocked-out position. The injection device 7 may indicate to the userthat it is has completed dispensing and the full dose has been deliveredto the patient with the button 77 in the up position and indicatorwindow 101 showing the injection device is empty. For example, when thebutton 77 is in the up position and indicator 101 shows a differentcolor such as but not limited to red, this may indicate that theinjection device 7 has completed the injection.

Referring to FIGS. 29-31, the injection device 7 may have an actuator orbutton 77 that the user depresses on the injection device 7 to start theinjection. The button 77 may be configured to be an on/off switch, i.e.,to only have two states, open and closed such as a light switch. Thismay prevent the user from pushing the button 77 half way and notactuating the injection device 7. Once activated, this ‘light switch’type button 77 would insert the needle 85 rapidly into the skin 99,independent of the user manipulation of the button 77. Alternatively,the button 77 could have a continuous motion, allowing the user toslowly insert the needle 85 into skin 99. The button 77 may preferablybe directly coupled to the needle 85 by using adhesive 104 creating abutton 77 and needle 85.

Referring to FIGS. 29-31, the injection device 7 may have a needle 85travel into the skin 99, upon actuation of the button 77 that initiallygoes to a first position or depth as shown in FIG. 30 and retractsslightly to a second position of depth preferably automatically as shownin FIG. 31. The first depth shown in FIG. 30 is achieved from overtravel of the button 77 during actuation. The first depth may becontrolled by features 105 in the button 77 in direct contact with thebase 106 of the injection device 7. The final depth of the needle 85 issuitable for subcutaneous injections. Alternatively, the final depth ofthe needle 85 may be reduced for intradermal injections. Alternatively,the final depth of the needle 85 may be increased for intramuscularinjections. Upon reaching the first depth, the needle 85 retracts backto a second depth as shown in FIG. 31. The retraction distance of theneedle to the second depth is in the range of 0.1-2 mm. This retractionfeature is preferable to prevent the needle 85 from being blocked bytissue during the initial insertion process. This tissue blockage couldrequire a very high pressure to overcome and prevent the injectiondevice 7 from delivering the drug. The retraction of the needle 85 fromthe first position to a second position creates an open pocket ahead ofthe needle tip 107 allowing reduced pressure for initiation of flow ofdrug from the needle 85. This reduced pressure for initiation of theflow of drug from the needle is preferable for the injection device 7 tomaintain a relatively constant pressure during injection.

Referring to FIGS. 29-31, the injection device 7 may include a needle 85with a side hole 108. As shown in FIG. 31, once the button 77 on theinjection device 7 is fully depressed, the needle 85 will be fullyinserted into the skin 99 through the dispense port 82 and the injectiondevice 7 will begin dispensing of the injectable. Until the button 77 isfully depressed, the side-hole 108 and therefore the internal lumen ofthe needle 85 is not in communication with the fluid channel 86 of thedispense port 82. Both the side-hole 108 and needle-tip 107 are retainedwithin a septum 109. With the side-hole 108 and needle-tip 107 beingretained within the septum 109, the entire drug path is kept sterileuntil the time of use. When the button 77 is fully depressed and theneedle 85 is in the dispense position, a side hole 108 in the needle 85is in communication with the fluid channel 86 of the dispense port 82and the injection of the liquid begins.

Referring to FIGS. 29-31, the septum 109 provides the advantage ofsealing the needle tip 107 as well as the side hole 108 from theinjectable before and after dispense. Sealing the needle tip 107 and theside hole 108 of the needle 85 at the end of the injection has aparticular advantage to prevent dripping of injectable from theinjection device 7 after end of dispense and/or after it is removed fromthe skin surface. It also prevents contaminates from entering the hollowneedle prior to being actuated into the skin. The septum 109 may be madeof any suitable material to allow for sealing once the needle 85 haspunctured it. The material composition of septum 109 may preferably besilicone. Alternatively, the material composition of the septum may alsobe a blend of different materials including but not limited tobromobutyl, chlorobutyl, isoprene, polyisoprene, SBR, polybudtadiene,EPDM, natural rubber and silicone. Alternatively, the fluid pathway 86including the dispense port 82 could be a rigid plastic with a siliconeinjected overmold to produce the septum previously described.

Referring to FIGS. 29-31, the septum 109 at the dispense port 82 couldprotrude slightly from the underneath surface into the skin surface 99of the injection device 7 to provide for pressure on the skin surface 99at the injection site. This pressure on the skin surface 99 by thedispense port 82 after the needle is retracted could eliminateinjectable from coming out of the injection site commonly referred to asblowback.

Referring to FIGS. 29-31, the injection device 7 may include a set ofspring tabs 110 that interface with the button 77 to perform lockingfunctions. A spring tab 110 is biased to lock into an undercut 111 inthe button 77 to keep the button 77 in a first up position or pre-fireposition as shown in FIG. 29. The geometry of the undercut 111 andspring tab 110 help to produce the light switch actuation forcedescribed previously. This light switch actuation is accomplished by thetranslation of the button 77 relative to the spring tab 110 and thegeometry of the mating undercut 111 surfaces.

Referring to FIGS. 29-31, the injection device 7 may include a springtab 112 that interact with the button 77 in the injection device 7 toperform locking functions such that when the button 77 is actuated tothe first depth and retracts slightly back to the second depth ordispense position, undercut features 113 in the button 77 allow a springtab 112 to hold the button 77 in the dispense position until theinjection device 7 has completed dispensing.

Referring to FIGS. 32-33, the injection device 7 may include an end ofdelivery indication or empty indicator 114 to sense when all of thefluid 79 has been expelled from the expandable member 78 and theinjection device 7 has completed dispensing. The empty indicator 114 maybe configured with a slot or other opening 115 to slide over theexpandable member 78 at the exit port when the expandable member 78 isin a deflated state after all of the fluid has been expelled. There maybe two states of the empty indicator. As shown in FIG. 32, the emptyindicator may be in a first position or deflected-out state when theexpandable member 78 is full with fluid 79 at that section and is notcontained within the slot or opening 115. This first position wouldtranslate to a non-empty state of the expandable member 78 when thediameter of the expandable member 78 is larger than its minimum due toresidual fluid 79 contained within. As shown in FIG. 33, the emptyindicator 114 may be in a second position or deflected-in state when theexpandable member 78 is partially or fully contained within the slot oropening 115. This second position would translate to an empty state ofthe expandable member 78 when the diameter is at a minimum.

Referring to FIGS. 32-33, the injection device 7 may include anautomatic needle retraction mechanism at the end of dispense. Thismechanism includes a direct coupling between a spring tab 112, buttonundercut feature 113 and the empty indicator 114, all previouslymentioned. When the expandable member 78 is filled with injectable 79and the button 77 is depressed from a first pre-fire position to asecond dispense position as shown in FIG. 33, undercut features 113 inthe button 77 allow a spring tab 112 to hold the button 77 in thedispense position until the injection device 7 has completed dispensing.This spring tab 112 may also be directly coupled to the empty indicator114 which is naturally in the first position or deflected-out state. Themotion of depressing the button 77 to a second position or dispenseposition allows a post feature 116 in the button 77 to provide a bias orpre-tension on the spring tab 112 to urge the empty indicator 114 to itssecond position or deflected-in state. However, since the expandablemember 78 is initially full with injectable 79 at a large diameter, theempty indicator 114 cannot move to the second position or deflected-instate as shown in FIG. 32. After the button 77 is depressed, the fluid79 starts to expel out of the expandable member 78 through the needle aspreviously mentioned. Once the expandable member 78 has expelled all ofthe fluid 79 and is at a minimum diameter, the empty indicator 114(under pretension from the spring tab 112) will move to the secondposition or deflected-in state as shown in FIG. 33. The spring tab 112directly coupled to the empty indicator 114 also moves with the emptyindicator 114. This movement releases the spring tab 112 from theundercut feature 113 in the button 77 to allow the button 77 (andneedle) to move up to a final position or post fire position after thedispense is completed as shown in FIG. 34.

Referring to FIG. 34, lock out spring tabs 117 may also interact withthe button 77 in the injection device 7 to perform locking functionssuch that when the injection is complete the button 77 is released, andthe button 77 is urged up by the return spring 118 to a final upposition or post-fire position. The button height 77 relative to the topof the injection device 7 in the final up position or post-fire position(shown in FIG. 34) may be higher than the pre-firing position (shown inFIG. 29). The end of the lock out spring tabs 117 move out to the outerdiameter surface 119 of the button 77 within the outer housing 74 tolock the button 77 in the up position or post-fire position and preventthe button 77 from being actuated again.

Referring to FIG. 34, the injection device 7 may include a return spring118 that interacts with the button 77 to provide a bias to the button 77into a first up position or pre-fire position. When the button isactuated down to a second depth or dispense position, the return spring118 is compressed causing more of a bias or preload. At the end of thedispense period, the button 77 is unlocked from the second depth ordispense position (shown in FIG. 31) to move up to a final position orpost fire position after the dispense is completed as previouslymentioned. It is the bias of the return spring 118 that forces thebutton 77 up to a final position or post-fire position.

Referring to FIG. 34-35, upon removal of the injection device 7 from theskin 99, the injection device 7 will preferably be locked out,preventing non-destructive access to the needle or reuse of theinjection device 7. The injection device 7 may indicate to the user thatthe full dose has been delivered. This indication could be in the formof a visual indictor, audible sound, mechanical movement or acombination.

Referring to FIG. 35, upon removal of the injection device 7 from theskin 35, a bandage 120 may release from the injection device 7 andremain on the skin surface 35. This can be affected by using an adhesiveon the bandage portion that more strongly attaches the bandage to theskin than the adhesive that attaches the bandage to the injection device7. Thus when the housing is lifted from the skin, the bandage 120remains in place over the injection site as described in U.S. Pat. No.7,637,891 and U.S. patent application Ser. No. 12/630,996, filed Dec. 4,2009 incorporated by reference herein.

Referring to FIGS. 36-39, the injection device 7 may preferably includea manifold 121 that assembles to both the expandable member 78 and thefilling port 81 and dispensing ports 82, and provides direct fluidcommunication between the expandable member 78 and the filling 81 anddispensing 82 ports of the injection device 7. The manifold 121 may beconfigured on the end that assembles to the expandable member 78 to belarge in diameter to facilitate filling and expelling all of the fluid79 out of the expandable member 78 as previously discussed. The manifold121 may preferably include internal passageways 122 to allow for fluidflow in and out of the expandable member 78. The manifold 121 may beconfigured with a filter 123 in the injectable fluid pathway 122 forfiltering the injectable 79 to remove particulate before and after it isintroduced into the expandable member 78. The filter 123 may be amembrane, depth filter or other suitable filtration media that is ofsufficiently small pore size or effective pore size to removeobjectionable particulate, which may include but not be limited toundissolved injectable 79 in those situations where the injectable 79 isreconstituted by the transfer apparatus. The manifold 121 may also beconfigured with a filter 123 for the removal or air. Such an air removerfilter 123 may include a bubble trap, air gap of other configuration inthe injectable fluid pathway 122 that removes air from the injectablefluid pathway 122 before it is introduced into the expandable member 78.This air remover filter 123 may be configured with a hydrophobic filteror a combination of hydrophobic and hydrophilic filters. A hydrophobicfilter would allow for the venting of air from the transfer apparatusbut not the passage of liquid. A hydrophilic filter would allow thepassage of liquid but not the passage of particulate or air. The airremover filter 123 may also have check valves to allow for venting oftrapped air. Alternately, the air remover and filters 123 may be locatedat any point in the fluid pathway from the filling port 81 to the needle85. For example, the most downstream point in the fluid pathway is thedistal end 128 of the expandable member 78. An internal mandrel 124 maybe connected to distal end 128 of the expandable member 78. An airremover or filter 123 may be integrated into this downstream point toallow for venting of trapped air during filling of the injection device7. Furthermore, the mandrel 124 could include a slot along its lengththat is in communication with the downstream filter 123 to aid in theventing of air during the filling process.

Referring to FIGS. 36-39, the injection device 7 may include a resilientexpandable member 78 such as an elastomeric balloon or bladder. Thematerial composition of expandable member 78 may preferably be silicone.Alternatively, the material composition of the expandable member 78 mayalso be a blend of different materials including but not limited tobromobutyl, chlorobutyl, isoprene, polyisoprene, SBR, polybudtadiene,EPDM, natural rubber and silicone. In addition, the expandable member 78may be coated to improve their surface properties. Coatings may includeparylene, silicone, Teflon and fluorine gas treatments. Alternatively,the expandable member 78 may be made from a thermoplastic elastomer.

Referring to FIGS. 36-39, the injection device 7 may include a resilientexpandable member 78 which the injectable 79 is transferred underpressure. This causes the expandable member 78 to enlarge and theresilience of the expandable member 78 creates a pressure which tends toexpel the injectable 79. The pressure chamber of the transfer apparatusdescribed previously (or such other pump or pressurizing means as may beemployed in the transfer apparatus) transfers the injectable 79 to theinjection device 7 under pressure. Introducing the injectable 79 intothe expandable member 78 under pressure causes it to stretch and expandboth in diameter and length. An example of this would be blowing up along, skinny balloon. The volume range of the injection device 7 may be0.5 to 30 milliliter. When expanded, the resilient expandable member 78exerts an expulsion pressure in the range of 1 to 200 psi on theinjectable 79 contained in the expandable member 78 so that theinjection device 7 is ready to administer the injectable 79automatically when triggered by the user by depression of the button aspreviously described. Thus, the transfer apparatus as previouslydescribed operates not only to transfer a measured amount of injectable79 (and if necessary mix, dilute and filter it) to the injection device7, but also simultaneously charges or provides the motive pressure tothe injection device 7 (by expanding the resilient expandable member 78)so that the injection device 7 is ready to automatically dispense theinjectable 79 under the pressure exerted by the resilient expandablemember 78 when actuated by the user.

This aspect of the transfer apparatus (simultaneous transferring andcharging) is particularly beneficial. While the above applications showthe injection device 7 in a pre-filled or charged condition forinjection of the drug 79 when the injection device 7 is actuated, thepresent disclosure contemplates that the injection device 7 can remainempty and the expandable member 78 in a more relaxed and unfilledcondition, i.e., in a non-charged or non-filled condition, untiladministration of the injectable 79 is required. Only then is theinjectable 79 mixed or processed as necessary and introduced into theinjection device 7, expanding the expandable member 78 to a filled(charged) condition. In the present disclosure, the drug is stored inits original container closure (vial) until the time of use. Because theinjectable 79 will typically be injected within seconds to hours aftertransfer from the vial into injection device 7, shelf life and materialcompatibility of the drug with the materials in the fluid pathway withinthe injection device 7 are not significant issues. The challenges andexpense of designing an injection device 7 and selecting materials foran extended shelf life of pre-filled injection device 7 aresignificantly reduced.

Referring to FIGS. 36-39, the present subject matter may use features ofthe injection device 7 described in the patent applications incorporatedby reference herein as previously described. However, the expandablemember 78 employed in the injection device 7 here may also preferablytake the form of an elongated balloon or bladder arranged, for example,in a planar helical or spiral configuration as illustrated. Aspreviously mentioned, the injection device 7 includes a circular shapedouter housing 74 that has a spiral slot or recess 125 formed therein.The elongated balloon or bladder 78 rests in the slot 125, with one endfor communicating directly or indirectly with an injection needle 85through fluid pathways 122 and the other end for communicating directlyor indirectly with a dispense indicator 101. The elongated spiralconfiguration allows the balloon or bladder 78 to have substantialvolume for such quantity of injectable 79 as may be desired, while alsocontributing to the low profile configuration of the injection device 7.In other words, by utilizing a relatively long expandable member 78 witha large length to diameter ratio, very high pressures and volumes can beachieve with a minimum of forces required. Additionally the volume ofthe expandable member 78 can be changed by changing the filling length,without significantly altering the pressure/volume curves of theexpandable member 78.

Referring to FIGS. 36-39, one of the other aspects described in U.S.patent application No. 61/704,922, filed Sep. 24, 2012, that may beemployed in the present subject matter is the use of an insert or plugor mandrel 124 within the expandable member 78 to pre-stress theexpandable member 78 to a slightly expanded position when unfilled, sothat when the expandable member 78 expels the injectable 79, it willcontract or collapse to a condition where it is still stretched orstressed and continues to exert pressure on any fluid there within asshown in FIGS. 38 and 39. This better assures that all or substantiallyall of the injectable 79 is fully expelled from the injection device 7.The mandrel or shaft 124 could be a fluid filled expandable member ifdesired. This would allow for a variable size mandrel 124.Alternatively, the expandable member 78 could have a sufficiently smallinternal volume (small diameter) when unstressed so that virtually allthe injectable 79 is expelled without the need for and internal mandrelor shaft 124. Additionally, the expandable member 78 could beflattened/stretched by ‘wrapping’ it around a surface within theinjection device such as a cylindrical wall 134. The pre-stress createdin the expandable member 78 would act to eliminate any residual fluidvolume remaining within.

There are a number of different ways to cause an expandable member 78 toexpand and/or contract in an arcuate manner as previously described.Referring back to FIG. 34, one way is to design the expandable member 78with a thicker wall cross section 126 in one area around thecircumference of the expandable member 78 that would cause theexpandable member 78 to expand in a circular fashion. Alternatively, aseparate element 126 could be affixed along the length of the expandablemember 78 to effectively stiffen the expandable member 78 in thatportion of the circumference that would cause the expandable member 78to expand in an arcuate manner. Referring back to FIG. 36, another wayis to use internal features such as slots or recesses 125 in the housing74 of the injection device 7 to guide the expandable member 78 around acircular or spiral path. These features 125 could interact with theexpandable member 78 in a number of ways, the simplest being the outershape of the expandable member is constrained by a slot 125 in thehousing 74 of the injection device 7. Friction between the expandablemember 78 and the inner surfaces 125 of the housing 74 could be reducedby lubricating the outside surface of the expandable member 78, or byinserting the expandable member 78 within a low spring rate spring thatwould limit both the friction and outer diameter of the expandablemember 78 while not constraining the length.

Referring to FIGS. 36-39, the elongated expandable member 78 may bepreferably configured to expand along an arc with a predetermined tubediameter without the aid of walls or a guide within the injectiondevice. Referring back to FIG. 34, looking at a cross-section of theelongated expandable member 78, a thicker wall area 126 in a smallportion of the circumference of the expandable member 78 may be added tocause the elongated expandable member 78 to expand in an arc aspreviously described. The arcuate expandable member 78 grows in lengthdue to increase in pressure and volume there within; the thicker section126 deflects less than the thinner section.

Referring to FIG. 36, the arcuate expandable member 78 will expand inlength in an arc shape as to orient its heavy wall thickness zone 126 orless deflecting zone to the inside of the circle. Increasing the wallthickness 126 of the expandable member 78 within the small zone 126around the circumference will effectively continue to decrease theradius of the arc of the expandable member 78. The increase in wallthickness 126 may be achieved by molding or extruding it into thearcuate expandable member 78 or by bonding a strip of material to oneside 126 of the expandable member to cause that portion of the wall 126to lengthen at a slower rate, thereby causing the expandable member 78to expand in an arc shape as previously discussed.

Referring to FIG. 37, the distal end of the expandable member 78 couldbe affixed an element such as an indicator 101, which is constrained tofollow guide path within the inner surfaces 125 of the housing 74.Alternately, the expandable member 78 could be pre-stretched andflattened around a circular diameter inside the injection device 7 suchas wall 134 so that there would be no change in expandable memberlength. Alternatively, a straight or curved mandrel 124 whose length ismore than the unstressed expandable member could be used to stretch theexpandable member into a circular shape within the injection device 7prior to filling. Alternatively, the mandrel 124 could be used as avisual indicator to show the state of the injection device 7 and theprogress of the injection. The mandrel 124 could be colored to allow itto be easily viewed through the housing.

Referring to FIGS. 36-39, the injectable 79 is injected into theexpandable member 78 by the transfer apparatus and the expandable member78 is expanded to a certain outer diameter controlled by theconfiguration of the inner surfaces 125 of the housing 74. In this way,the entire length of the expandable member 78 can be filled with a knownvolume of drug, and the outer diameter is known at each lengthwiselocation along the expandable member 78. It is desirable to have theexpandable member 78 fill and empty along its length in a controlledway, from one end to the other to encourage the expandable member 78 tocompletely empty, and to allow the easy and accurate measurement offluid 79 in the expandable member. To visually aid in determining howmuch fluid 79 is in the expandable member 78, graduated markings couldbe printed on the expandable member 78, like a syringe, to indicate thevolume remaining in the expandable member 78. As previously describedand referring to FIGS. 21-22, the expandable member 78 and housing 74could be clear to allow the user to see the drug 74 and the volumeremaining in the injection device 7. Alternatively, graduated markings127 could be printed on the housing 74 to indicate the volume remainingin the expandable member 78.

Referring to FIGS. 36-39, in accordance with an aspect of this subjectmatter mentioned above, the injectable 79 is preferably expelledprogressively from the distal end 128 of the elongated expandable member78 toward the proximal end 129. The proximal end 129 of the expandablemember is closest to the dispensing needle 82 or cannula. This allowsthe user to visually ascertain or approximate the injection statusvisually alone or with the aid of graduation markings 127 on theinjection housing 74, the window 80 or the expandable member 78.Progressive expulsion may be achieved in a variety of ways. For example,the injectable 79 exits the expandable member 78 at the manifold 121 atthe proximal exit port section 130 and is preferably located at theproximal end 129 of the elongated expandable member (e.g., balloon orbladder). The thickness of the wall of the expandable member 78 may bevaried, uniformly or stepwise increased, along its length from thedistal end 128 toward the proximal end 129. Due to restraint by thewalls of the spiral channel 125 in which the expandable member 78resides, the expandable member 78 would be inflated with injectable 79to a substantially uniform diameter along its length. However, thethicker wall at the distal end 128 of the expandable member 78 wouldexert greater contraction force on the injectable 79 than the thinnerwall at the proximal end 129 and thus collapse or contract in diameterfirst during expulsion of the injectable 79. The expandable member 78would then collapse progressively from the distal end 128 toward theproximal end 129 as the wall of the expandable member 78 becomes thinneralong its length in that direction. Because the thickness of theexpandable member 78 preferably substantially uniformly increases fromthe proximal end 129 toward the distal or closed end 128, thecontractive force of the expandable member 78 wall when expanded willincrease substantially uniformly along the length of the elongatedexpandable member 78 from the proximal port end 129 to the distal orclosed end 128. Thus, when the injectable 79 is expelled into thesubject, the expandable member 78 will progressively collapse indiameter as well as shrink in length, which collapse in diameter andshrinkage in length is preferably viewable by the user as describedabove. The distal end 128 of the elongated expandable member may allowfor the connection of a movable indicator component 101 in the injectiondevice 7 which will follow the shrinkage in length of the elongatedexpandable member 78. This indicator 101 is preferably viewable by theuser through the outer housing 74 and indicates the state of theinjection device 7 and the progress of the injection. Alternatively, theexpandable member 78 is configured with a constant wall thickness andcould be prestressed in manufacturing to bias it to fill from theproximal end 129 to the distal end 128 and collapse or empty from thedistal end 128 to the proximal end 129 in a progressive manner aspreviously discussed.

Referring to FIGS. 36-39, the elongated expandable member 78 of theinjection device 7 may be configured to have a section 130 of theexpandable member 7 adjacent to the proximal exit port end 130 thatfills first and collapses last during filling and expulsion of theinjectable 79 from the injection device 7. In other words, duringfilling of the injection device 7 by the transfer apparatus, it isadvantageous to have the most proximal exit port section 130 of theexpandable member 79 to fill with injectable first. Additionally, duringdispense of the injectable 79 from the injection device 7, it isadvantageous to have the last remaining volume of injectable 79 to becontained within the most proximal exit port section 130 the expandablemember 79. There are several advantages to the abovementionedconfiguration. The proximal end section 130 of the expandable member 78could have a thin wall that would cause it to remain inflated under alower pressure than the rest of the expandable member 78. This wouldassure that the section 130 of the expandable member 78 would remaininflated until all injectable 79 had been expelled from the rest of theexpandable member 78. As previously discussed, this section 130 may bedirectly coupled to an empty indicator to provide for full or emptyindication. Additionally, as previously mentioned, this section 130could be mechanically coupled to the empty indicator to allow for theautomatic withdrawal of the button 77 and needle 82 upon completeexpulsion of the injectable 79.

Referring to FIGS. 36-39, alternatively or in addition to varying thewall thickness 126 of the expandable member 78, an elongated internalmandrel or shaft 124 within the expandable member 78 may progressively(linearly or stepwise) decrease in cross-sectional size along the lengthof the expandable member 78 from proximal end (the exit port end) 129toward the distal end (closed end) 128 of the expandable member 78.Additionally, the manifold 121 which allows for attachment of theexpandable member 78 to the injection device 7 may also be configuredwith a large diameter section 130 at the proximal end 129 of theexpandable member 78. A large diameter section 130 of the mandrel 124 ormanifold 121 at the proximal end exit port 129 of the expandable member78 insures that the expandable member 78 will fill with injectable 79 inthis area 129 first. In other words, the expandable member 78 is beingheld at nearly a fill diameter at the proximal end exit port 129 by thelarge diameter section 130 of the mandrel 120 or manifold 121. As fluid79 first starts to fill the expandable member 78, it reaches a filldiameter first in the large diameter section 130 then fillsprogressively along the length of the expandable member 78 from theproximal end 129 to the distal end 128 as previously discussed.

Referring to FIGS. 36-39, as previously discussed, during dispense ofinjectable 79 from the expandable member 78, the diameter of theexpandable member 78 at its distal end continuously collapses in aprogressive fashion (similar to deflating a long skinny balloon) fromits distal 128 to proximal end 129 until all of the fluid is expelledfrom the expandable member 78. A large diameter section 130 of themandrel 124 or manifold 121 at the proximal end exit port 129 of theexpandable member 78 provides the same benefit (as previously describedfor filling) during dispense of the injectable 79. This large diametersection 130 insures that the last remaining fluid 79 in the expandablemember 78 will be contained and dispensed from this area 130. Aspreviously discussed, this section 130 may be directly coupled to anempty indicator to provide for full or empty indication as well as forthe automatic withdrawal of the button 77 and needle 82 upon completeexpulsion of the injectable 79.

Operation and Method

Referring to FIGS. 40-42, the sterile injection device 7 is attached tothe transfer apparatus 3 within a covered tray 132 and a separatelypackaged vial holder 2 with filled vial(s) is provided in a carton 131.The user places the carton 131 on a clean, flat surface. The user opensthe lid 133 to the carton 131 to expose the transfer apparatus 3 andvial holder assembly 2. The user removes the cover 132 from the transferapparatus tray 3 to expose the transfer apparatus 3 and injection device7. The user is instructed to leave the transfer apparatus 3 in thecarton 131 and only remove the injection device 7 when prompted.

Referring to FIG. 43-44, at the time of use, the user will remove thevial holder assembly 2 from the carton 131. The user will then removethe vial cap from the vial using the attached cap remover. The user willinsert the vial holder 2 into the transfer apparatus 3. The user willpush the vial holder 2 with attached vial 16 into the transfer apparatus3 to actuate the system 1. This will do three things in the illustratedembodiment. First it will lock the vial holder 2 with attached vial 16into a down position within the transfer apparatus 3. Then it willautomatically initiate fluid communication between the contents 23 ofthe vial 16 and the transfer apparatus 3 by introducing an access memberthrough the septum of the vial. Third it will initiate the mixing (ifneeded) and transfer sequence of the transfer apparatus 3. This sequenceof events will occur automatically and require no additional input bythe user to proceed.

Referring to FIGS. 45-47, in a dual vial system 4 where mixing isrequired; the user may have the ability to adjust the delivery dose. Adose selector 48 is moved from an initial position shown in FIG. 46 to afinal delivery volume position in FIG. 47. At this point, the vialholder 5 is free to depress by the user allow for the mixing andtransfer to initiate. First, the diluent fluid is transferred from thediluent vial and introduced into the powdered lyophilized injectablevial. The fluid will be introduced into the powdered vial in such a wayso that when the fluid is transferred from the vial, all the powder isremoved as well. Mixing of the diluent and powder may occur completelyin the powdered vial, or may be completed in the transfer apparatus.Static or dynamic mixing elements may be incorporated into the transferapparatus or introduced into the powder vial by the transfer apparatusto allow for adequate mixing of the powered drug or other injectable anddiluent. The mixing may take up to several minutes to complete. Themixing will be done in as gentle a way as possible to minimizebubbles/foaming and shear stresses in the mixture. The mixing also willbe done in such a way to encourage the powder to be completely mixed,and no particles are present. In-line filters, valves or other means maybe employed to remove particles or air. There may be an indicator on thetransfer apparatus showing that mixing is progressing.

Referring to FIGS. 45-47, in a dual vial system 5, the reconstitutedsolution is mixed in the powdered vial or transfer apparatus 6, a setvolume of solution prescribed by the manufacturer or set by the user isautomatically transferred into the pressure dose chamber. This setvolume is then automatically transferred to the injection device 7. Thetubes, conduits valves and any other volume of the fluid path betweenthe vials and transfer apparatus 6 will be minimized to encouragetransfer of the maximum percentage of the drug to the injection device7.

Referring to FIGS. 48-50, once the required dose volume has beendelivered to the injection device 7, there is a clear area or otherindicator 80, 101 in the injection device 7 to allow the user to viewthe mixed solution to verify complete mixing. Ideally, the user couldview the entire drug volume within the injection device 7. There couldalso be an indicator 101, such a relative fill gage, to show that thecorrect dose had been delivered to the injection device 7. Completion ofthe mixing and transfer to the injection device 7 would then ‘unlock’the injection device 7 and allow it to be removed from the transferapparatus 3, 6 or injection device docking station. The injection device7 may indicate to the user that it is in a ready state with the button77 in the up or ready position and the indicator window 80, 101 showingthe injection device is full.

Referring to FIG. 50, the user may disconnect the injection device 7from the transfer apparatus 3 by twisting or pulling the injectiondevice 7 off of the transfer apparatus 3. During removal of theinjection device 7, an adhesive tape liner may be removed automaticallyexposing an adhesive surface on the bottom of the injection device thatmay be used to adhere the device to the patient's skin. Alternatively,the tape liner may have a tab that the user pulls to manually removebefore adhering the device to the skin.

Referring to FIG. 51, the user attaches the injection device 7 to theirskin 99. There may be an adhesive on the bottom of the injection device7 that allows for adhesion to the skin 99 surface and hands-freeoperation. The adhesive may extend past the outline of the injectiondevice to allow the user to firmly adhere the tape to the skin.Alternatively, the user may hold the injection device 7 against the skin99 for the duration of the injection.

Referring to FIGS. 51-53, the user removes the safety 100 and depressesthe button 77 on the injection device 7 to start the injection. Once thebutton 77 on the injection device 7 is fully depressed, it is lockedinto place and the needle will be fully inserted into the patient andthe injection device 7 will begin dispensing the injectable drug. Theinjection device 7 may alert the user that injection of the drug hasstarted. This alert could be in the form of visual indictors, audiblesounds, mechanical movements or a combination. The time of the injectioncould be in a range of a few seconds to several hours. The injectiondevice 7 may indicate to the user that it is dispensing with the button77 locked in the down position and indicator window 101 showing theinjection device 7 is less than full. The injection device 7 preferablyhas a clear section 80 that allows the user to easily determine theamount of drug remaining in the injection device 7.

Referring to FIG. 54, the user will be alerted when the injection of thedrug is completed. This alert could be in the form of visual indicators,audible sounds, mechanical movements or a combination. The injectiondevice 7 may indicate to the user that it is has completed dispensingwith the button 77 moving to a locked up position with tactile andaudible sounds and indicator window 101 showing the injection device isempty. At the end of the dispense, the needle will automatically retractinto a locked position within the injection device 7.

Referring to FIG. 54, upon removal of the injection device 7 from theskin 99, a bandage 120 could release from the injection device 7 andremain on the skin surface 99. Upon removal from the skin 99, theinjection device 7 will preferably be locked out, preventingnon-destructive access to the needle or reuse of the injection device 7.The injection device 7 may indicate to the user that the full dose hasbeen delivered. This indication could be in the form of a visualindictor, audible sound, mechanical movement or a combination.

In accordance with further aspects of the present subject matter, whenadministering an injection with a syringe and needle that is meant to beinfused under the skin, it is desirable to know if the needle isproperly placed within the skin or improperly placed within a bloodvessel. It is common for a user performing an intradermal (ID),subcutaneous (SC) or intramuscular (IM) injection to aspirate thesyringe by pulling back on the plunger to create a pressure drop withinthe syringe to see if any visible blood comes up the needle into thesyringe. If blood is visualized, this means the tip of the needle is ina blood vessel. A number of injectable drugs meant for infusion underthe skin specifically indicate not to inject into a blood vessel. Bloodaspiration using a syringe and needle is a common technique and can beperformed by anyone with adequate training. However, as more drugs arebeing presented in automatic injection devices, the ability to manualaspirate these types of systems does not exist. Once an injection deviceis placed on the skin and the needle is fired, there is no way for theuser to know if the needle is properly placed within the skin orimproperly placed within a blood vessel. Accordingly, there exists aneed for a blood aspiration device and method within an automaticinjection device.

Referring to FIGS. 55-56, the injection device 7 may have a needle 85with a side-hole 108 in operative engagement with the button 77 slidablewithin a septum 109 advancing into the skin 99. The button 77 may have aviewing window 160 on the button top 103 that is in fluid communicationwith the proximal end 161 of the needle 85. The button top 103 mayinclude a cavity 162 for blood 159 to accumulate and be seen through thebutton window 160 by a user. The cavity 162 may include a center hole163 that allows fluid communication with the proximal end 161 of theneedle 85 via needle lumen 165. The outer walls 164 of the cavity 162are formed by the button top 103. Additionally, a portion of the outerwalls 164 may include a hydrophobic filter 166. In this configuration,the proximal end 161 of the needle 85 is at atmospheric pressure. Iffluid 14 or blood 159 travel up the internal lumen 165 of the needle 85,it exits the proximal end 161 of the needle 85 and fills the cavity 162.The air 167 in the cavity 162 is easily displaced through thehydrophobic filter 166 until all of the air 167 has been displaced fromthe cavity 162 and it is full of fluid 14 or blood 159. At this point,the flow of fluid 14 or blood 159 stops as the fluid 14 or blood 159cannot penetrate the hydrophobic filter 166 and can be easily viewedthrough the window 160 of the button top 103 by the user thus providinga method for determining if the injection device 7 needle 85 is in ablood vessel 158.

Referring to FIG. 57, needle insertion into tissue can be generallydivided into four stages. These include no contact, boundarydisplacement, tip insertion and shaft insertion. During boundarydisplacement, the tissue boundary in the contact area deflects under theinfluence of the load applied by the needle tip, but the needle tip doesnot penetrate the tissue. The boundary of the skin follows the tip ofthe needle up to a maximum boundary displacement point in the contactarea as the needle tip starts to penetrate the skin. After the needletip penetrates the skin, the shaft is inserted into the tissue. Evenafter tip and shaft insertion, the boundary of the skin surface in thecontact area does not return to its original no contact state butremains displaced by a distance x. The amount of boundary displacement xis a function of several parameters including but not limited to needlediameter, needle tip geometry, needle shaft friction, needle insertionspeed and physical skin properties. Boundary displacement x of the skinin the contact area is characterized in needle-based injection devicesbecause it effects how much of the needle penetrates the skin andtherefore reduces the actual needle penetration depth by the amount ofboundary displacement x. If the boundary displacement x could beintentionally induced by stretching or preloading such as pushing theskin out at the contact site prior to needle tip insertion, there wouldbe no additional boundary displacement by the needle tip or shaft duringinsertion and the needle tip depth could be predictably defined. Theadvantage of this intentional displacement is the amount of needlepenetration into tissue would not be affected by variations in theboundary displacement x. Without intentionally inducing boundarydisplacement at the skin surface prior to needle tip insertion, theactual needle penetration depth into the skin is not specifically knownbecause some of the needle length (depending on the abovementionedparameters) is outside the skin due to the naturally occurring boundarydisplacement x shown in FIG. 57. On the other hand, if the maximumboundary displacement could be induced at the contact site, the actualneedle penetration depth would not change with the variations in theabovementioned parameters including needle diameter, needle tipgeometry, needle shaft friction, needle insertion speed and physicalskin properties.

Referring to FIG. 58, the injection device 7 may have a skin boundarydisplacement extension or structure, such as an underside surface 76that includes an extension 138 at or around the dispense port 82 or aspart of the dispense port 82. The extension extends substantially normalto plane of the tissue at the point of needle insertion. When theinjection device 7 is attached to the skin 99, the extension 138 willprotrude against the skin 99 surface resulting in displacement orcompression of the skin 99 in this contact area 139. The compression ofthe skin helps to reduce or eliminate “tenting” of the tissue surfaceupon needle insertion. In other words, by “preloading” the tissue bycompressing it, the extension 138 serves to eliminate further tissuedefection or tenting, or results in more reproducible and lesser amountof skin surface deflection or tenting. During actuation of the button 77from a pre-fire state to first position, the needle 85 advances out ofthe injection device 7 through the dispense port 82 and/or extension 138into the skin 99 to start the dispense of drug. For the reasonsdescribed above, as the needle 85 advances out of the injection device7, the tip of the needle 107 does not produce additional boundarydisplacement 141 (already intentionally induced by the extension 138) inthe skin 99 at the contact area 139. Thus the actual needle penetrationdepth 140 into the skin 99 is better characterized and controlled. Also,the extension, through which the needle passes, compresses the tissueimmediately around the needle, which has several advantages. During theinjection, the compression of the tissue by the extension 138 in thecontact area 139 increases the local density of tissue thus creating ahigher pressure zone compared to the surrounding adjacent tissue 99. Asinjectable enters the skin 99, the fluid will migrate from this highpressure zone 139 to lower pressures areas in the skin 99 which helps toprevent injected fluid or drug from flowing or migrating into theimmediate area around the needle/skin puncture site and acts to reduceor minimize fluid leakage (backflow) and/or bleeding from the puncturesite. This higher pressure zone also effectively provides the benefit ofa much longer injection needle. Experimental data confirms this. In anultrasound evaluation comparing the subcutaneous deposition depth of a10 mL fluid bolus (saline) using the injection device 7 with a 5 mmneedle depth and an off-the-shelf infusion pump (Freedom 60, RMS) with abutterfly needle extension set (9 mm needle depth), results show thatthe subcutaneous depth of the 10 mL bolus, post injection was equivalentbetween the injection device 7 with a 5 mm needle length and the pumpwith a 9 mm needle length. In all results, bolus position wascharacterized by distance (Zd) from the skin surface to top edge ofbolus. FIG. 103 shows the top edge of the 10 mL subcutaneous bolus usingthe pump with 9 mm needle length. The Zd distance was measured at 0.44cm. FIG. 104 shows the top edge of the 10 mL subcutaneous bolus usingthe injection device 7 with a 5 mm needle length. The Zd distance wasmeasured at 0.42 cm. Thus, a similar depth of the bolus is provided witha needle depth (5 mm) and the tissue displacement structure that is morethan 40% shorter than the other tested needle (9 mm) without a tissuedisplacement structure.

Another advantage of the extension 138 is compression of the tissue inthe contact area 139 after the injection has completed. In thepost-fired state, the button 77 has popped up alerting the user that theinjection device 7 has completed. The needle 85 is fully retracted outof the puncture hole in the skin 99. The dwell time between when theinjection device 7 has completed dispense and is removed by the user canbe several minutes or more, depending on the environment in which theuser is in at the time of completion. For the same reasons describedearlier, the compression of the tissue by the extension 138 in thecontact area 139 increases the local density of tissue thus creating ahigher pressure zone compared to the surrounding adjacent tissue 99.Similar to how a nurse may apply pressure to an injection site withtheir thumb after injection, this pressure helps close the puncture holeand prevents injected fluid or drug from flowing back up the injectionsite and acts to reduce or minimize fluid leakage and/or bleeding fromthe puncture site.

Referring to FIG. 60, the vial access member 21 of the transferapparatus 3 maybe comprised of multiple lumens, such as multi-lumentubes 34 to communicate with the internal fluid pathways 35 of thetransfer apparatus 3. The vial access member 21 preferably comprises oneinlet tube 36 allowing air or fluid to enter the vial 12 and one outlettube 37 allowing for air or fluid to exit the vial 12. The lumenopenings 38 in the vial access member 21 can be oriented so the inlettube opening 36 is above the output tube opening 37 when the vial isinverted and attached as illustrated, for example, in FIG. 59. Thisorientation allows for introduction of air or liquid through the upperinlet tube 36 and output of the vial contents 14 through the loweroutput tube 37. Further, the outlet opening 37 may be positioned nearthe lower end bottom of the inverted vial 12, adjacent to the septum 19to encourage the entire contents 14 of the vial 12 to enter the outletport 37 and be removed from the vial 12. Once the vial 12 is installedin the vial holder docking area 29 in the transfer apparatus 3, the vialaccess member 21 is able to access the contents 14 of the vial 12. Whenthe transfer apparatus 3 begins to withdraw the contents 14 from thevial 12 through the outlet tube 37, a pressure drop 154 occurs in thevial 12. This pressure drop 154 causes displacement air 58 to be drawninto the vial 12 through the inlet opening 37 of the vial access member21 to replace the fluid 14 that is being withdrawn. In some casesdepending on the amount of injectable 14 in the vial 12, the liquidlevel 153 in the vial 12 may be above the vial access member 21 andspecifically above inlet tube opening 37. When air 58 is drawn into thevial 12 through the inlet opening 37, it creates a bubble 155 in thefluid 14. Buoyancy causes the bubble 155 to migrate to the top of thevial 12 with the existing air 58. In some injectables 14, it isundesirable to introduce air bubbles 155 into the solution. This causesmore bubbling, frothing and or foaming within the fluid 14.

Referring to FIG. 61, an extension member 156 could be slideablymoveable within the inlet opening 36 of the vial access member 21. Theouter diameter of the extension member 156 may be close fitting to theinner diameter of the inlet opening 36. The extension member 156 mayhave an inner diameter that allows air 58 to pass through it. When air58 is drawn into the vial 12 through the inlet vent opening 36 due tothe pressure drop 154 in the vial 12, the air 58 first pushes theextension member 156 like a piston within the inlet opening 36. Theextension member 156 is sufficiently long as to not come out of theinlet opening 36. The extension member 156 continues to slide throughthe inlet opening 36 until the end of the extension member 156 stops atthe top 157 of the vial 12 well above the liquid level in the vial 153.The top of the inverted vial 12 acts as a stop to the extension member156. The tip of the extension member 156 may be tapered as to not blockflow through its inner diameter when in contact with the top of theinverted vial 12. Air 58 continues to travel through the inner diameterof the extension member 156 until all of the fluid 14 in the vial 12 hasbeen withdrawn from the vial 12 through the outlet tube 37. Aspreviously mentioned, the outer diameter of the extension member 156 isclose fitting to the inlet opening 36 inner diameter as to not allow airto leak between this interface. The extension member 156 insures that noair 58 is introduced into the liquid 14 within the vial 12 causingbubbles 155.

Referring to FIG. 62, the pressure chamber 59 may be configured with aninlet port 168 used to bring fluid 14 and air 58 into the chamber.Additionally, the pressure chamber 59 may be configured with an outletport 64 used to expel fluid 14 and/or air 58 out of the chamber 59.These ports 168, 64 may be positioned off-center of the pressure chamber59 to help control the sequence of liquid 14 and air 58 introductioninto and/or expulsion from the pressure chamber 59. As previouslymentioned, the outlet port 64 of the pressure chamber 59 may be orientedbelow the inlet port, during the process of expelling the liquid 14 fromthe pressure chamber 59, all of the liquid 14 is expelled first then theremaining air 58 is expelled last any air in the chamber 59 would beoriented to the top of the pressure chamber 59. Additionally, as shownin FIG. 62, the exit port profile 169 may be configured in anon-circular shape to further encourage the entire liquid contents 14 ofthe pressure chamber 59 to enter the outlet port 64 and be removed fromthe pressure chamber 59 prior to removal of air 58 from the pressurechamber 59. Additionally, as shown in FIG. 62, a portion 170 of theoutlet port 64 may be positioned below the surface 171 of the pressurechamber 59. This may act as a trap to further encourage the entireliquid contents 14 of the pressure chamber 59 to enter the outlet port64 and be removed from the pressure chamber 59 prior to removal of air58 from the pressure chamber 59.

Referring to FIG. 63, when liquid 14 is removed from a vial 12 using avial access member 21, only fluid 14 through the outlet opening 37 isremoved until the liquid level 153 drops to the top of the outletopening 137. At this point, a mixture of liquid 14 and air 58 will beremoved. Referring to FIG. 63, the vial access member 21 mayadditionally have an outlet opening 37 configured in a non-circularshape such that the opening height is reduced and the opening width isincreased to further allow for more liquid content 14 of the vial 12 toenter the outlet port 37 and be removed from the vial 12 prior toremoval of air 58 from the vial 12.

Referring to FIGS. 64 and 65, the combination of hydrophobic 68 andhydrophilic 69 filters in the fluid pathway 35 between the vial 15 andthe injection device 7 may preferably allow for filtering of drug 14 andremoval of air 58 during the transfer process. These filters may beseparate components or combined into one component. Each filter may beconstructed from different materials including but not limited to MixedCellulose Ester (MCE), Polyvinylidene Difluoride (PVDF),Polytetrafluoroethylene (PTFE), Nylon and polyethersulfone (PES). Eachfilter may have a range of pore sizes from 0.22 to 3 micron. Each filtermay have a coating to make it hydrophilic or hydrophobic.

When administering an injection that is meant to be infused under theskin, a common reaction is infusion site swelling. This reaction isparticularly pronounced in single subcutaneous sites where the infusionvolume is high and/or the infusion rate is fast. When these infusionsare administered with a syringe and needle or administration set,infusion site swelling has no consequence to the injection device.However, as more drugs are being presented in automatic injectiondevices that are adhered and worn on the body during the infusion, siteswelling presents a challenge in keeping the automatic injection devicesecured to the body. In particular, the lump or bulge formed by theinfused solution at the skin surface may dislodge an automatic injectiondevice from the infusion site if the adhesive on the injection device isnot properly designed. Accordingly, there exists the need for anautomatic injection device with properly designed adhesive that allowsfor bulging at the injection site without compromising the adherence ofthe device to the patient.

Referring to FIG. 66, there are two interfaces related to adhering theinjection device 7 to the skin 99. The first is the adhesive/deviceinterface 173 and the second is the adhesive/skin interface 174.

Referring to FIG. 67, the adhesive 88 could be configured on theinjection device 7 with at least two zones. The first zone 175 mayinclude a permanent bond using mechanical or chemical means between theadhesive 88 and the injection device 7 and preferably be positionedwithin the perimeter of the injection device 7. The second zone 176 maybe configured to be detachable or unattached from the injection device 7and preferably be adjacent and on the outside (e.g., radially outward)of zone 1.

Referring to FIG. 68, if the adhesive 88 were completely attached to thebottom 76 of the device 7, during a tissue bulge 177 event the adhesive88 at the adhesive/skin interface 174 would start to peel from the skin99 because this interface 174 is weaker than the adhesive/deviceinterface 173. This is demonstrated on a bulging surface in FIG. 68.This may result in the injection device 7 becoming dislodged from theskin surface 99 and falling off the patient.

Referring to FIGS. 67 and 69, instead of permanently attaching theadhesive 88 completely to the bottom 76 of the injection device 7 asshown in FIG. 68, the adhesive 88 could be configured on the injectiondevice 7 with the abovementioned zones 175, 176. During a tissue bulgeevent 177 in this configuration, the adhesive 88 in zone two 176 woulddetach from the injection device 7 and be firmly attached to the skin 99surface at the adhesive/skin interface 174. This would allow fortransfer of the peel edge 178 from the adhesive skin interface 174 tothe adhesive/device interface 173 effectively creating a strain reliefat the adhesive/skin interface. The adhesive/device interface 173 may bedesigned to be much stronger and prevent injection device 7 separationfrom the skin surface 99.

When performing self-injections with automatic injection devices,protecting the user from accidental needle sticks is a beneficialrequirement for the device. Typically, the needle is retracted withinthe device before and after use, preventing the user from accessing theneedle. However, during the injection, the needle is extended outside ofthe device. If the automatic injection device were body worn andinadvertently fell off the user during the injection, the needle wouldbe exposed creating a potential needle stick hazard to the user.Accordingly, there exists the need for an automatic injection devicewith a skin dislodgement sensor to automatically retract a needle if thedevice becomes dislodged from the skin during the injection.

Referring to FIG. 70-72, a skin dislodgement sensor 179 may be inoperative engagement with a flexible latch 181 of the button 77 andslidable within the lower housing 180 of the injection device 7.Referring to FIG. 71, when the injection device 7 is attached to theskin surface 99, the skin dislodgement sensor 179 is forced into a firstor up position 182 inside the injection device 7. When the button 77 isactuated to a fired state or second position or dispense position(exposing the needle 85), the flexible latch 181 is forced into a lockposition 187 by the skin dislodgement sensor 179 under the latch board183. The latch board 183 holds the button 77 at the latch board surface184 on the button 77 down in the fired state or dispense position untilthe end of dispense. At the end of dispense, the latch board 183translates away from the latch board surface 184 on the button 77,allowing the button 77 and needle 85 to retract to a post fire positionwhere the needle 85 is contained within the injection device 7.Referring to FIG. 72, in the event that the injection device 7 becomesdislodged from the skin surface 99 during injection, the skindislodgement sensor 179 extends to a second or down position 185 out ofthe injection device 7. This allows the flexible latch 181 to springback to an unlocked position and disengage from the latch board 183.This allows the button 77 and needle 85 to retract to a post fireposition where the needle 85 is contained within the injection device 7.

When performing self-injections with a syringe and needle, users mayhave the need to temporarily stop or pause the injection due to acutepain or irritation at the injection site. This pause in flow ofinjectable into the injection site, accomplished by removing pressure onthe plunger rod of the syringe, helps to reduce the pain at theinjection site by allowing the injectable fluid bolus more time todiffuse into the surrounding tissue and thus reducing the local pressureand associated pain and irritation. However, as more drugs are beingpresented in automatic injection devices, the ability to manually pausethese types of automatic systems does not exist. Once an automaticinjection device is placed on the skin and the cannula is introduced,there is no way for the user to pause the injection due to pain orirritation at the injection site. Accordingly, there exists a need for auser to be able to pause an automatic injection system.

Referring to FIGS. 73-74, upon actuation of the button 77, the needle 85and button 77 travel to a first position or depth as shown in FIG. 73.In this first position or depth, the side-hole 108 is covered by theseptum 109 and therefore the internal lumen 165 of the needle 85 is notin communication with the fluid channel 86 of the dispense port 82. Thebutton 77 may be intentionally held in this first position or depth toprevent flow of injectable 14 from the fluid channel 86 into theside-hole 108 of the needle 85 and into the skin 99. As shown in FIG.74, when the button 77 is released, the needle 85 and button 77 returnto a second position or dispense position where the side-hole 108 isexposed to the fluid channel 86 allowing the flow of injectable 14 fromthe fluid channel 86 into the side-hole 108 of the needle 85 and intothe skin 99 until the end of the injection. This action of pushing thebutton 77 to the first position or depth may be performed as many timesa necessary during the entire injection.

Referring to FIGS. 75-76, the button 77 actuation force 186 is thetransition load applied to the button 77 required to start displacementof the button 77 and needle 85 from a pre-fire position to a fired stateor dispense position. Until this transition load is met, the force 186applied to the button 77 is transferred directly to the injection device7. Specifically, this load 186 may be transferred to adhesive skininterface 174 and/or the adhesive device interface 173 resulting inbetter securement of the injection device 7 to the skin surface 99 priorto actuation of the injection device 7.

Referring to FIG. 77, an indicator window 172 on the transfer apparatus3 may be present to show that the transfer of fluid 14 and/or mixing isprogressing. This indicator window 172 could be configured in the baseof the transfer apparatus 3 and track the movement of the plunger 93 ofthe pressure chamber 56 within the transfer device 3. The indicatorwindow 172 could be configured with a scale or other means to track themovement of the plunger 93. Alternatively, the plunger 93 could beconfigured with a different color to make it easy to track its movementin the indicator window 172. The combination of the indicator window 172and plunger 93 could provide the progress of withdrawing fluid 14 fromthe vial 12 and filling of the chamber 56. The combination of theindicator window 172 and plunger 93 could also provide the progress ofthe transfer of fluid 14 from the chamber 56 to the injection device 7.

Referring to FIG. 78-79, the arcuate expandable member 78 is positionedand/or will preferably expand in length in an arc shape. In theillustrated embodiment, the arc shape is induced by providing a lessresilient area for example a thicker or relatively heavy wall thicknesszone 126 which will result in less deflection of the expandable memberin that zone and result in formation of an expanded arc shape. Thisheavy wall thickness zone 126 may be configured in any shape that willallow for the arc shape in the expandable member 78 during expansion. Apreferred configuration for the heavy wall thickness zone 126 is tominimize its thickness or attachment 150 in the circumferentialdirection on the expandable member 78 wall and maximize the radialthickness or projection 151 away from the expandable member 78. Thisserves to urge the expandable member 78 to expand in an arc shape butalso maximizes the amount of material along the circumference that isunaffected by the heavy wall thickness zone 126 for expansion.Additional features including but not limited to a T-shape may beconfigured to the end of the radial projection 152 to help urge theexpandable member 78 into an arc shape.

Referring to FIG. 80, the volume of the pressure chamber 56 could be setto be larger than the total fluid volume 14 in the vial 15 so thatadditional air 58 is drawn into chamber 56 from the vial 15. Thisadditional air 58 could be helpful in insuring that all of the liquid 14is removed from the vial 15 and removal or clearing of residual liquid14 in the fluid pathways 35 between the vial 15 and the chamber 56.Additionally, during transfer of the liquid 14 from the chamber 56 tothe injection device 7, the additional air may be useful in the removalor clearing of residual liquid 14 in the fluid pathways 35 between thechamber 56 and the injection device 7.

Referring to FIG. 81, the transfer apparatus 3 comprises a vial holderdocking area 29 that may include an elongated vial access member orpiercing member 21. This vial holder docking area 29 may include a vialaccess protector 136. The vial access protector 136 is locked and heldin a first position above the vial access member 21 by locking fingers137 within the vial holder docking area 29 prior to insertion of thevial 12 or vial holder to cover the vial access member 21 and preventinadvertent vial access member stick by the user. When the vial 12 orvial holder is inserted into the vial holder docking area 29, the vial12 or vial holder displaces the locking fingers 137 and unlocks the vialaccess protector 136. Once unlocked, the vial access protector 136 ismovably slidable within the vial holder docking area 29 with the thevial 12 or vial holder.

Referring to FIG. 82, flow restrictors 55 may be used in the fluidpathway 35 to control and/or delay the transfer time and/or increase themixing time. Small lumen tubing could be used at any point in the flowpath 35 to restrict flow and increase the time of mixing/transfer fortimes up to an hour or more. One method to control and/or delay thetransfer time and/or increase mixing time between the second pressurechamber 42 and the injection device 7 is by the use of multi-lumen fluidpathways 142 between the second pressure chamber 42 and injection device7. Each lumen 143, 144 of the fluid pathway 142 is attached to aspecific location 145, 146 on the second pressure chamber 42, preferablyspaced apart along the travel of the piston and has an internal diameter147, 148 sized to provide for a specific flow rate through that lumen143, 144 based on the pressure within the second pressure chamber 42.Initially as the second pressure chamber piston 46 starts its advance inthe chamber 42, the fluid mixture 14 is dispensed through all of thelumens 143, 144 in the fluid pathway 142 to the injection device 7. Oncethe piston passes over an attachment point 145 between a lumen 143 andthe pressure chamber 42, the flow of fluid through that lumen 143 stopsand fluid 14 is forced through the remaining lumen 144. Multiple lumensand attachment points could be positioned along the pressure chamber.The final lumen 144 available from flow of fluid 14 could be sized withan internal diameter 148 that is very small. Accordingly, the flow ratewould be very low, increasing the time to transfer the fluid 14 from thechamber 42 to the injection device 7. This delay of transfer allows forincrease mixing time.

Referring to FIG. 83, a safety, such as a safety pin or safety sleeve100 may be configured to allow for removal from the injection device 7in any direction to release the injection device 7 to be ready to fire(inject).

Referring to FIG. 84, the injection device 7 includes a needle 85 with aside-hole 108 that allows for fluid communication between the fluidchannel 86 and the skin 99 once the button 77 is fully depressed in theinjection device 7. This starts dispense of the injectable 14. The innerdiameter 165 of the needle 85 is significant in controlling the rate ofdispense from the injection device 7. Referencing the Hagen-Poiseuilleequation for fluid flowing in a pipe, the flow rate through a pipe isdirectly proportional to the radius of the pipe to the fourth power.Thus, small variations in the inner diameter 165 of the needle 85 resultin large variations in flow through the needle 85, especially as theinner diameter 165 gets smaller. The needle 85 in the injection device 7may range from 21G to 34G (Stubs Iron Wire Gauge System) in various wallthickness configurations. This range corresponds to an inner diameter165 range of 0.021″ to 0.003″, recognizing that there is manufacturingvariation or tolerance with the needle inner diameter 165 in any givenneedle size. This is based on needle size and can have an inner diametervariation as much as ±0.00075″. To limit the range of the inner diameter165 within any given needle size and resulting variation in flow, theneedle 85 may be modified prior to assembly into the injection device 7.This modification could include crimping, flattening or rolling theneedle to a new, prescribed effective inner diameter 165 over a portionof the length of the needle 85 from a circular shape to a non-circularshape. This has the advantage of allowing for specific delivery ratecontrol from the injection device 7.

Referring to FIGS. 85-86, the lumen openings 38 in the vial accessmember 21 can be oriented to allow for introduction of pressurized airor liquid through the upper inlet tube 36 and output of the vialcontents 14 through the lower output tube 37. Further, the outletopening 37 may be positioned near the bottom of the inverted vial 12,adjacent to the septum 19 to encourage the entire contents 14 of thevial 12 to enter the outlet port 37 and be removed from the vial 12. Thepreferred sequence for removal of the contents 14 from the vial 12 isfirst all of the fluid 14 in the vial 12 and then the air 58 from thevial 12. This is achieved with the current embodiment when theorientation of the transfer apparatus 3 is oriented as shown in FIGS.85-86. Based on the geometry of the vial access member 21 within thevial 12, this sequence of all fluid 23 then air 58 removal is achievedup to transfer apparatus 3 angles of +/−45 degrees from horizontal.Beyond this angle, there is the possibility that air 58 is introducedbefore or during fluid 14 removal from the vial 12. An angle sensor 149may be positioned in or around the vial access member 21 to sense theangle of the transfer apparatus 3. It may have direct communication witheither or both of the lumen openings 38 and/or each or both of the inlettube 37 and output tube 36. In the current embodiment as shown in FIG.85, when the transfer apparatus 3 is at an angle less than 45 degrees,the sensor 149 allows fluid communication between the outlet port 37 andthe fluid pathways 35. As shown in FIG. 86, if the transfer apparatus 3were tilted to an angle greater than 45 degrees, the sensor 149 mayrotate or translate to a new position to shut off the fluidcommunication between the outlet port 37 and the fluid pathways 35.

Referring to FIG. 87, an alternative transfer apparatus 3 within asingle vial system that does not perform mixing but only transfers fluid14 from a single vial 12 to the injection device 7 is provided. Thisalternative transfer apparatus 3 includes a vial 12, a variable volumepressure chamber 56 and fluid pathways 35 to direct the contents 14 fromthe vial 12 into the injection device 7. The inlet tube 36 of the vialaccess member 21 is connected to the variable volume pressure chamber 56with fluid pathways 35. The outlet tube 37 of the vial access member 21is connected to the injection device 7 through fluid pathways pressurechamber 56.

Referring to FIG. 87, the full insertion of the vial 12 into thetransfer apparatus 3 by the user causes the introduction of the vialaccess member 21 through the septum 19 of the vial 12 to access thecontents 14 of the vial 12. This also triggers the release of thepressure chamber trigger 59. The plunger 60 is in a retracted positionand the pressure chamber 56 is full of air 135. The pressure releasetrigger 59 releases the plunger 60 within the pressure chamber 56connected to a dispense spring 63. The dispense spring 63 advances theplunger 60 and displaces air 135 from the pressure chamber 56 into thesingle vial 12 though the inlet tube 36. Air 135 entering the vial 12displaces the fluid 14 out of the vial 12 through the outlet tube 37into the injection device 7. This continues until all of the fluid 14 isdisplaced out vial 12 into the injection device 7. Check valves 40 couldbe employed to prevent fluid 14 from going back into the vial 12 orfluid 14 from going back into the pressure chamber 56.

Syringe Contents Transfer

The present subject matter is directed, in part, to a disposable,one-time-use apparatus and methods for preferably transferring, uponuser initiation, the injectable contents of one or more standardsyringes into an injection device and preferably simultaneouslypressurizing the injection device for subsequent automated injectioninto a subject. The apparatus and method described herein may be of anysuitable detailed configuration, but is preferably configured totransfer the contents of a syringe into an injection device. Theapparatus and method may employ any of the features or aspects describedabove, alone or in combination with the features or aspects describedbelow and/or show in the attached figures. Also, the apparatus may beconfigured to allow the user to select a dose volume to be transferredto the injection device and subsequently delivered to the subject. Theapparatus may further be configured to filter the contents for removalof particulate or drug particles before transfer into the injectiondevice, and may include a sterile filter for filtering any displacementair captured in the syringe or syringes. The apparatus may further beconfigured with one-way valves to only allow the user to transferinjectable from the syringe into injection device. Also, the apparatusmay further be configured with one-way valves to prevent pressurizedinjectable in the injection device from flowing back into the apparatusat the filling port. The apparatus may also include a lockout to preventthe user from removing the injection device prior to drug transfer orfrom activating the injection device until the device has been removedfrom the transfer apparatus.

At the time of use, the user inserts the filled syringe into the syringereceiving area. The user depresses the syringe plunger or piston tomanually transfer the injectable through the transfer apparatus into theinjection device. This simultaneously charges the injection device(e.g., expanding and pressurizing the expandable member or balloon byintroducing the injectable thereinto under pressure) so that theinjection device is ready for automated injection into a subject uponuser activation.

Referring to FIGS. 88-90, the disposable, one-time use, manual syringetransfer and injection system 189 may comprise a transfer apparatus 190and injection device 7. Referring to FIG. 88, the transfer apparatus 190has, among other features, an outer housing or base 191 of rigid moldedplastic or other suitable material and defines a syringe docking area orfirst receiving station 192 for receiving a syringe such as a standardsyringe and an injection device docking station or second receivingstation 193 (for removable injection devices such as an injection deviceas previously described in detail above). In the illustrated structure,the syringe docking station 192, which may be in the form of acylindrical recess, and injection device docking station 193 are spacedapart, such as at opposite ends of the transfer apparatus housing 191.As in earlier embodiments and with the same benefit, the transferapparatus 190 may have an outer housing 191 that is integrated into thepackaging 194 of the system.

Referring to FIGS. 89-90, the transfer apparatus 190 has at least onefluid pathway 195 extending from a syringe connector port at one end218, such as a female luer syringe connector within the cylindricalrecess, and a port or outlet 219 at another end such as in the injectiondevice docking station for mating or connecting to an inlet of theinjection device. The fluid pathway 195 may be a single pathway orinclude an array of internal fluid pathways 195, as required to performany transfer of the injectable 196 and conveying or transferring it fromthe syringe 197 in the syringe docking area 192 to the injection device7 in the injection device docking station 193. The fluid pathway(s) 195may include flexible or rigid conduits or tubing 198 that form all orpart of the pathway. The fluid pathway(s) 195 may also include checkvalves, such as a check ball 199, to control fluid flow from the syringeto the injection device and to prevent backflow; one or more filters200, such as submicron filter membrane to filter the injectable 196during transfer to the injection device 7. The filter 200 may have othercharacteristics also, such as being hydrophilic to block air fromflowing to the injection device 7, or hydrophobic to connect the flowpath to a vent passageway and prevent fluid flow through the ventpassageway, flow restrictors or other means to convey, control and/ordirect the drug 196 from the syringe 197 through transfer apparatus 190,into the injection device 7.

Injectable Warming

A significant portion of injectable biopharmaceutical drugs require coldstorage conditions (typically 2-8° C.) for long-term stability. Thesedrugs must be maintained at this lower temperature until the time of useor risk therapeutic failure due to a lack of potency. Presently, at thetime of usage, patients are required to remove the drug from therefrigerator and allow it to naturally warm to ambient or roomtemperature, which can typically range from about 15 to about 32° C.,before administering. Depending on the drug container, e.g., packaged orunpackaged vial or pre-filled syringe, this process may take up toone-half hour or more. If the drug/device is not allowed to warm, thereare a number of potential problems. First, the drug viscosity canincrease by a factor of three or more because of the cold solutiontemperature, making the fluid more difficult to inject through a smallneedle into a patient. Second, if the device is electronically driven, acold battery can have a significantly lower energy and may not functionas well as desired. Third, a cold drug is significantly more painful forthe patient into whom it is injected. Also, users or patients may not becomfortable allowing their injection devices to remain out and in theopen for warming for an extended period of time because of concernsabout child safety, concerns that they might forget about it, and/ordesires to go about their business when they simply don't want to waitfor 30 minutes or more to leave their home.

A number of devices are currently being marketed for active heating ofrefrigerated drug/device combinations. Actively heating the drugsolution using a heater, e.g., electrical heater, or other technique (attemperatures above room temperature) may add cost to the product and mayresult in overheating and subsequent degradation of the drug,representing an additional expense and complication for the user. Thus,a passive system and method that quickly, reliably and safely warm coldor chilled injectables, allowing the user to conveniently use itpromptly, right out of the refrigerator, would be very beneficial forthe reasons outlined above.

In accordance with further aspects of the present subject matter,referring FIGS. 91 and 92 as well as the other figures, for illustrativepurposes only, passive heat transfer can take place from theroom-temperature transfer device 203 and injection device 206 structureand from the environment 201, including from room or ambient temperaturegas the cold injectable 202. The heat transfer may take place in thetransfer device 203 (or the other transfer/injection devices describedherein), within the fluid pathways (generally designated 204) between,for example, the vial 205 or syringe and the injection device 206, bycontact with room or ambient temperature gas, and within the injectiondevice. Fluid pathways 204 may consist of tubes, conduits, filters,check valves or other components capable of carrying fluid and, morespecifically, may optionally be made of or in direct conductive contactwith material having high thermal conductivity. Such high thermalconductivity material may be a metal such as copper, stainless steel,aluminum or other metal, or non-metal material with high thermalconductivity, that is compatible with temporary contact with theparticular fluid. The fluid pathways may also be configured to enhanceor maximize heat-transferring contact between the fluid and the flowpath. This may be achieved by maximizing or enlarging the surface of theflow path in contact with the fluid and, more particularly, maximizingor enlarging the ratio of fluid path surface area to unit volume offluid, such as by increasing the length or reducing the cross-sectionalarea of the flow path. Also, the fluid pathways may be configured toenhance heat transfer by providing a flow path that has a relativelylarge high thermal conductivity mass or is contact with a relativelylarge high thermal conductivity mass. In particular, and as onenon-limiting example, the total mass of the material that makes up theflow path, such as high thermal conductivity material, and/or is indirect heat-conductive contact with a flow path, may be substantiallyequal to or greater than the total mass of the fluid being transferredso as to afford rapid and sufficient heat transfer rate and capacity.

The mass of the heat conductive flow path or contacting material is notthe only factor that may be considered in elevating drug temperatureduring transfer. For example, as mentioned above, the fluid flow pathcould be configured so that the ratio of the surface area contacting thefluid to a unit volume of fluid is sufficiently large so as to effectall or a portion of the desired heat transfer. Such a flow path could beconfigured to afford substantial heat transfer, even with a non-metallicflow path material, although high heat transfer material such as a metalor a material having a heat transfer rate comparable to metal mayprovide greater or faster heat transfer. Separately, or in addition, theflow path could be configured so that work is done (or energy isexpended) on the drug or other fluid in the flow path, which would causeadditional heating of the fluid. This is still considered passiveheating, as no electrical heating source is required and no heating at atemperature above ambient room temperature is used. For example, arelatively long flow path of very small cross-sectional size or diameterwould provide a relatively large surface area and enhance conductionbetween the surface of the flow path and the drug or other fluid flowingtherewithin. Such a system may also tend to increase the frictional orshear forces exerted on the fluid, which would serve to increase fluidtemperature. To flow liquid at a sufficient flow rate through such anelongated, small diameter flow path may also require significantpressurization of the fluid, such as by mechanical pump or pneumaticpressurization, which would also tend to raise the temperature of thefluid. These various features (flow path material, mass of fluid flowpath and contacting material, fluid flow path surface area, and energyexpended on fluid during flow through the flow path) may be usedseparately or in different combinations to obtain the desired heattransfer.

Further, one additional feature that can aid in heat transfer andraising chilled drug temperature is the use of near room or ambienttemperature gas to effect the fluid transfer and flow. In other words,the use of gas at room temperature or higher to force the drug or otherfluid to flow though the flow path may also contribute to heat transferand temperature rise. More specifically, the injection of nearly roomtemperature gas into a drug vial to force the drug therefrom will resultis some amount of heat transfer from the gas to the liquid drug. If thegas is also bubbled or otherwise passed through the vial contents, heattransfer from the room temperature gas to the fluid will be furtherenhanced. The injection of gas from a variable volume pressure chamberinto a vial to force fluid from the vial is described earlier withreference to FIGS. 9 and 10. The use of pre-filled pressurized gascylinders as the motive force for moving injectable through a transfersystem is also described in U.S. Provisional Patent Application Ser. No.62/138,762 filed Mar. 26, 2015, which is hereby incorporated byreference in its entirety. The present drug transfer and injectionsystems, as described in any of the examples or embodiments above, mayuse one or more of these heat transfer features, alone or incombination, to raise the temperature of a chilled drug.

For example, ambient or room temperature is typically about 15-32° C.,such as about 18-22° C. or about 20° C. Referring to FIGS. 92-93, in anambient temperature passive transfer device 203, refrigerated injectable202 of a selected volume (typically about 2-8° C., or about 4-5° C.) canbe transferred from the vial 205 or syringe through the fluid pathways204 and heat exchanging elements and structures 207 within the transferdevice 203 to the injection device 206 in a transfer time of fromapproximately 0.05 to up to 3 minutes or more. During this time, therefrigerated injectable, solution or other fluid 202 can absorb enoughheat energy from the ambient temperature fluid pathways 204, from theambient temperature gas (if used) driving the fluid and from the ambienttemperature heat exchanging elements 207 in the transfer device 203 andfrom the ambient temperature injection device 206 to reach a temperaturewithin about 5° C. or less of ambient or room temperature. Thetemperature increase may be in the range of at least 5-15° C., such asat least about 10-15° C. For example, a temperature increase from about4.5° C. to about 13-18° C. or about 16-18° C. in about 80 seconds orless, such as about 30-60 seconds may be achieved. This assumes that theinjectable 202 may be aqueous based, such as based on saline ordistilled water, although some light oils may be used with other drugs.The quantity of such injectable 202 for a single dose in accordance withthe present subject matter may range up to about 50 cc. Typically therange for a single dose may be between about 2 cc and 50 cc and may beless than about 5 cc, depending on the injectable and physicianprescription. The injectable viscosity may vary with the type ofinjectable and the temperature. For example, the injectable may have aviscosity up to about 100 cP.

Referring to FIGS. 92-93, the heat exchange between the ambientenvironment 201 and the cold injectable drug, solution or other fluid202 in the transfer device 203 may happen in a number of ways. Forexample, heat energy may be transferred to the chilled injectable fluid202 from the transfer device 203 through direct conduction within thefluid pathways 204 between the surface of the pathways and the fluid.The fluid pathways 204 may be configured with a relatively smalldiameter, and/or extended or long length to enlarge or maximize theamount of room temperature material surface area of the transfer and/orinjection devices in contact with the cold fluid or solution 202. Forexample only, the fluid flow pathway 204 could have a total length fromabout 0.5 inches to about 5 inches (1.7-12.7 cm), an inner diameterbetween about 0.01 and 0.1 inches (0.25-2.54 mm) and optionally an innerdiameter in the range of 0.01-0.05 inches (0.25-1.2 mm), preferablyabout 0.05 inches (1.2 mm). This range of flow path diameters (orequivalent cross-sectional areas if the flow pathway is not circular) isapplicable to all of the embodiments described above. As noted earlier,longer flow path length and smaller inner diameter (or cross-sectionalsize) provide more surface area for heat transfer from the ambientenvironment to fluid flowing through the pathway. The equivalentcross-sectional areas for a non-circular flow path are substantially asfollows:

Circular ID Equivalent Area 0.1 inch 0.00785 square inches 2.54 mm 5.064square millimeters 0.05 inch 0.00196 square inches 1.27 mm 1.266 squaremillimeters 0.01 inch 0.0000785 square inches 0.254 mm 0.0506 squaremillimeters

Heat energy may also be transferred to the cold fluid 202 throughconvection from the introduction of room temperature air, such asventing or displacement air, during the withdrawal of fluid 202 from thevial 205 or syringe. The materials of the fluid pathways 204 may becomprised of or in direct contact with thermally conductive metalmaterials to allow for more effective heat exchange between theenvironment 201 and the cold fluid 202, such materials includingaluminum, copper, and stainless steel or other material, with a thermalconductivity coefficient of about 45-385 W/mK. Fluid pathways 204 mayalso be comprised of thermally conductive polymers with enhanced thermalconductivity coefficient, such as 1-100 W/mK. Further, as describedearlier, heat energy may be transferred to the cold fluid 202 throughthe kinetic energy, friction and shear forces associated with movingfluid during the transfer process.

Referring to FIGS. 92-93, the fluid pathway, generally identified byreference number 204, is illustrated for purposes of description in theform of tubing, but could also be in preformed fluid flow paths moldedas part of the transfer device, or in such other form as may bepreferred. As illustrated, flow path section 204A extends from a vialloading station or port to a transfer or pressure chamber C. Fluid ordrug flow path section 204B extends from the pressure chamber C to aninlet into the heat exchanging member 207, which is optional. The heatconducting member 207 may comprise a large mass 207 of any of theabovementioned metals or plastics with geometries 208 so as to maximizethe ratio of fluid surface area to volume, and may be part of or incontact with materials in the fluid pathway 204. Heat exchanging member207 may include plural flow paths (see FIG. 93) or a serpentine flowpath, for example, to enhance contact between the fluid and the surfaceof the heat transfer member. The transfer device 203 may also containadditional heat exchanging elements 207 to enhance the heat exchangebetween the cold fluid 202 and the environment 201. Metal or plasticmeshes and/or filters 209 at room temperature may be positioned withinthe fluid pathway 204 to enhance the heat exchange between the coldfluid 202 and the environment 201. The cold fluid 202 could also bepassed through a matrix of heat conductive material such as a matrixformed of stainless steel balls or other small elements within the fluidpathway that allow a high surface area-to-mass contact with the fluid.From the heat exchanger or conductor 207, fluid flow path 204C extendsto an inlet or fill port for filling an injection device, such as theinjection device described in detail above.

FIGS. 100-102 are graphs depicting data from certain testing regardingthe warming of chilled fluid as it flows through a transfer system andinto an injection device similar to that shown in one of the abovedescribed transfer and injection devices. FIG. 100 shows the warming ofchilled aqueous-based fluid, such as distilled water, as compared tounaided room temperature warming temperature of a like fluid. The testwas conducted with a transfer device similar to the transfer device 203shown in FIGS. 91-93, and injection device 206 similar to that shown inFIGS. 68-76. The transfer device 203 provides for heat transfer from theenvironment 201 to the cold or chilled fluid 202 contained within thevial 205 as it transferred from the vial 205 to the injection device 206through fluid pathways 204, resulting in warming of the cold solution202 to near room temperature in significantly less time than unaidedwarming of the vial and reducing the time that a patient has to wait togive themselves an injection.

Drugs that require cold storage must normally be allowed to warm to roomtemperature before administration. The transfer and injection devicesdescribed herein provide for relatively prompt warming of the fluidafter removal from a refrigerator and without the wait required forunaided warming of a drug vial at room temperature. More specifically,FIG. 100 shows two datasets or graphs, 280 and 282, with temperature (°C.) on the Y axis and time (seconds) on the X-axis. The first dataset orgraph 280 represents the unaided warming of the aqueous-based fluidcontents of a standard glass vial 205 with the fluid contents 202starting at or near a range of 2-8° C. The vial contained a simulatedsingle injectable dose of 4 cc of fluid having a room temperatureviscosity of about 8 cP. The vial 205 was removed from the refrigeratorand a temperature monitoring system was inserted into the vial tomonitor the temperature of the solution. Therefore, the vial was used asa control comparison to generally model or represent a standard chilleddrug vial or a prefilled injection system (e.g., a prefilled syringe)which the user is instructed to remove from the refrigerator and let set(such as on a counter top) to gradually warm to room temperature beforeuse. FIG. 100, graph 280, shows such a normal first-order warming of thesolution as a function of time. As can be seen from the graph 280, fromthe time of removal from the refrigerator, approximately 20 minutes(1200 seconds) was required for the temperature of the fluid in the vialto rise to 21° C., with an average ambient room temperature of about23.8° C.

The second dataset or graph 282 in FIG. 100 is derived from a secondvial 205 of cold aqueous-based fluid 202 of the same volume transferredand dispensed from the transfer device similar to 203 (but without theheat exchanger 207) and injection device 206. Briefly, this attempted togenerally model the expected procedure followed by a patient, includingtransfer of the injectable from a vial, through the transfer apparatusand into the injection device, and dispensing from the injection device.The transfer device employed a PVC fluid flow tubing 204 having an ID ofabout 0.05 inches (1.3 mm), a flow path length from the vial to therigid plastic pressure chamber C of about 4.86 inches (12.3 cm), a flowpath length from the pressure chamber C to a filter (not shown) of about1.0 inches (2.54 cm) and from the filter into the expandable chamber orbladder in the injection device 206 of about 0.5 inches (1.27 cm). Asexplained earlier, the pressure chamber C is for effecting movement ofthe fluid from the vial, through the transfer apparatus and into theexpandable member or bladder 78 of the injection device 206. Dispensingfrom the injection device is through a 30 gauge needle.

Referring to FIG. 100, the second vial 205 with cold fluid 202 at 2-8°C. is removed from the refrigerator at time=0. The vial 205 is insertedinto the transfer device 203 to start the automatic transfer. The coldfluid 202 is transferred from the vial 205 through the fluid pathways204, the pressure chamber C and into the injection device 206. Once thetransfer is complete, the solution is dispensed from the injectiondevice 206. A temperature monitoring system measures the output streamtemperature of the fluid being dispensed from the injection device 206.In FIG. 100, this dispense starts at about t=80 seconds and is completedat about t=270 seconds. The fluid temperature is measured through theentire dispense process as shown in FIG. 100.

As can be seen in FIG. 100, as a result of transfer through the transferdevice 203 and into the injection device 206, both of which start atambient room temperatures of about 23.8° C., the temperature of thedispensing fluid has already reached about 21° C. within about 80seconds from removal from the refrigerator. Continued measurement showsthat the dispensed solution is between 21 and 22° C. for the entireperiod of dispense from beginning to end. As compared to the simulatedstandard chilled vial or chilled prefilled system, the time saved forthe patient with the present system is about 18 minutes. The rate oftemperature increase in the transfer apparatus and injection device are,on average, greater than about 10 times the rate of temperature increaseusing unaided ambient heating. This should contribute significantly topatient compliance, as the steps with the present system are relativelycontinuous and without long delays. In contrast, allowing a vial to siton a counter for 20 minutes until it warms (as in the unaided ambientwarming procedure) invites patient forgetfulness or distraction, whichcan easily result in a missed or untimely treatment or injection.

Testing was also done to simulate the system of FIGS. 88-90, and isreflected in FIG. 101. As shown there, the manual syringe system 189also provides for heat transfer to the injectable 196 in the syringe 197and as it transferred from the syringe and into the injection device 7through fluid pathways 195, allowing chilled drug or other solution toreach near-room temperature prior to dispensing from the injectiondevice. FIG. 101 shows two datasets or graphs 284 and 286 withtemperature (° C.) on the Y axis and time (seconds) on the X-axis. Thefirst graph 284 is from a standard glass vial 205 with coldaqueous-based fluid 202 of the same volume and viscosity (4 cc, 8 cP) asemployed in the data reported in FIG. 100, at or near a range of 2-8° C.when removed from a refrigerator. The vial 205 is removed and atemperature monitoring system is inserted into the vial to monitor thetemperature of the solution. This is the control and simulates aprefilled system injection system in which the user is instructed toremove from the refrigerator and let set out to warm to room temperaturebefore use. FIG. 101 graph 294 shows a normal first-order warming of thesolution as a function of time, and shows that warming by exposure to aroom temperature of about 24.2° C. (such as by simply sitting on acounter top in the room) required about 23 minutes.

The second dataset or graph 286 in FIG. 101 is based on the removal ofinjectable 196 from a second vial 204 of cold fluid 202 of like volumeand viscosity transferred and dispensed from the manual syringe system189 and injection device 7, both of which start at ambient roomtemperature of about 24.2° C. Referring to FIG. 101, a room temperaturestandard syringe 197 of rigid plastic material is used to withdraw coldinjectable fluid 196 from a second vial 205 at 2-8° C., removed from therefrigerator at about time t=0. The syringe with injectable fluid 196 isinserted into the manual syringe system 189 to start the manualtransfer. In FIG. 89, the cold injectable 196 is transferred from thesyringe 197 through the fluid pathways 195 into the injection device 7.The solution or fluid is transferred through standard PVC tubing havingan ID of about 0.050 inches (1.3 mm) and a flow path length of about 3inches (7.6 cm), from the syringe to the injection device and into theexpandable member or bladder 78 of the injection device. In actualapplications, the flow path could also include check valves, filters,and the like.

After the transfer is complete, the solution is dispensed from theinjection device 7. A temperature monitoring system measures the outputstream temperature of the fluid being dispensed from the injectiondevice 7. As seen in FIG. 101, this dispensing starts at about 80seconds after removal of the vial from the refrigerator. The dispensedfluid temperature is measured through the entire dispense process asshown in FIG. 101, which dispense is completed at about 350 seconds (5.8minutes).

As can be seen in FIG. 101, the fluid or solution is near roomtemperature even at the beginning of dispense from the injection deviceand is between about 19° C. and 20° C. during the entire injection. Theequivalent start of dispense at the same temperature (19-20° C.) withthe unaided warming of a simulated prefilled system compared to thepresent embodiment results in a time savings using the current system ofapproximately 13 minutes.

Referring to FIGS. 88-90, a repeated test was performed on an injectablefluid 196 in a syringe (not a vial) stored in a refrigerator. FIG. 102shows two datasets or graphs 288 and 290 with temperature (° C.) on theY axis and time (seconds) on the X-axis. The first dataset or graph 288is from a standard rigid plastic syringe 197 with aqueous-basedinjectable fluid 196 (4 cc volume, 8 cP viscosity), such as distilledwater, stored in a refrigerator at or near a range of 2-8° C. Thesyringe 197 with injectable fluid 196 is removed and a temperaturemonitoring system is inserted into the syringe to monitor thetemperature of the solution. This is the control and simulates aprefilled system injection system in which the user is instructed toremove from the refrigerator and let it set out, such as on a countertop, to warm to room temperature before use. In FIG. 102, the firstdataset or graph 298, shows a normal first-order warming of the solutionas a function of time.

The second dataset or graph 290 is derived the removal of a secondstandard rigid plastic syringe 197 with aqueous-based injectable fluidor solution 196 of like volume transferred and dispensed using themanual syringe system 189 and injection device 7, both starting atambient room temperature of about 24.2° C. Referring to FIG. 102, thesecond syringe 197 with injectable 196 is removed from the refrigeratorat t=0. The syringe with injectable 196 is inserted into the manualsyringe system 189 to start the manual transfer. As shown in FIG. 89,the cold injectable 196 is transferred from the syringe 197 through thefluid pathways 195 into the injection device 7. The general dimensionsare as described earlier for the use of this system. After the transferis complete, the solution is dispensed from the injection device 7. Atemperature monitoring system measures the output stream temperature ofthe fluid being dispensed from the injection device 7. In FIG. 102, thisdispense starts at about t=80 seconds. The fluid temperature is measuredthrough the entire dispense process as shown in FIG. 102, and is betweenabout 17° C. and 18° C. during the entire dispense, which is completedat about 5 minutes after removal of the chilled syringe from arefrigerator. The equivalent start of dispense at about the sametemperature (17-18° C.) with the unaided warming of a simulatedprefilled system compared to the current embodiment results in a timesaving of about 13 minutes for the current system.

Radiofrequency Compliance Monitoring

According to the National Council on Patient Information and Education(NCPIE), “Lack of medication adherence is America's other drug problem”.Lack of medication adherence (filling/refilling prescriptions on time)and compliance (taking prescriptions on time or as prescribed) by thepatient complicates what otherwise can be a normal progression back togood health. Further, lack of medication adherence and compliance addssignificant cost to an already burdened health care system withadditional medical costs and doctor's visits as well as extendedhospital stays. Thus, the success of a medication in the treatment of acondition relies on whether the prescription was filled and regularlytaken as instructed. Currently, this is the responsibility of thepatient alone. However, even well intentioned patients may accidentlyforget to take the medication or intentionally stop when the symptoms oftheir condition start to improve. Thus, a mechanism to alert thepatient, the prescriber, the healthcare provider or another third partyparticipant when non-compliance or non-adherence is occurring would bevery beneficial to permit intervention or reminder for the reasonsoutlined above.

In accordance with further aspects of the present subject matter, whenadministering an injection with an automatic injection device, it isdesirable to know when the prescription for the injection device wasinitially filled or refilled as well as whether the injection device wasused properly and on time. While many prescription drugs are tracked atthe time they are filled by the patient using specialized labeling,there are limited options to confirm if the patient actually took themedication. As more drugs are being presented in injection devices, theability to automatically track prescription initiation currently haslimited usage. Further, the ability to automatically track whether theinjection device was used properly does not exist.

As described herein, automatic tracking both for adherence andcompliance is accomplished wirelessly using RF (radio frequency)techniques installed within or in cooperative association the transferand/or injection devices described herein. Current technology allows forthe use of radio-frequency identification (RFID) to transfer data, forthe purposes of automatically identifying and tracking tags ormicrocircuit chips attached to objects. As used herein, RF or RFID or RFtags or RF chips are used comprehensively and interchangeably and areintended to include wireless electronic tags or chips for transmittingdata/information using any suitable wireless communication protocol ortechnology, such as Bluetooth or any other wireless technology.

RF tags or chips may be active or passive. While both types use RFenergy communicate between a tag or transponder and a reader, the methodof powering the tags is different. Active RFID uses an internal powersource (such as a battery) within or associated with the tag tocontinuously power the tag and its RF communication circuitry, whereaspassive RFID relies on RF energy transferred from the reader to the tagto power the tag. In the present subject matter, the injection device orthe transfer package may include an RFID tag, may optionally include apower source for the tag and be read or received by an external reader.In one embodiment, the RF tag or chip is removably associated with theinjection device such that it can be physically removed from theinjection device when the injection device is used. This allows for thesubsequent disposal of the injection device free of the limitations orrestrictions that might apply if the tag or chip remained as part of theinjection device after its use.

Referring to FIGS. 94-95, the injection device 210 may include an RF tagor chip 211 to monitor the injection device 210 status. For example, theRF tag 211 may broadcast to an external reader 212 (if active) orpresent (if passive, read by an external reader 212) information orstatus—such as “the injection device 210 has been prescribed,” “theinjection device 210 has been removed from its packaging,” and “theinjection device 210 has been actuated” and/or “the injection device 210has completed its dose.” The RF tag reader could also be associated withor in communication with an on-site or off-site data collectionfacility, such as by wireless or hardwired connection to allowrecordation and compilation of information regarding compliance.

Referring to FIGS. 94-95, an RF tag 211 may be used to monitor whetherthe injection device 210 has been activated or has initiated orcompleted its dose. The injection device 210 may include an active orpassive RF tag or chip 211 at any suitable location. As shown below,when used internally of the injection device, the RF tag or chip 211 maybe attached to the button 213 and in slideable communication with thespring tabs 214 during the first and second positions of the button 213.While the RF tag 211 is in slideable communication with the spring tabs214, the RF tag 211 may broadcast (if active) or present (if passive,read by an external reader 212) a first state to include an unusedstatus. In the event the injection device 210 is activated, the button213 is depressed to the dispense position. At the end of the dispenseperiod, the button 213 is unlocked from the second depth or dispenseposition (shown in FIG. 95) to move up to a final position or post fireposition. At this post-fire position, the RF tag 211 may no longer be incontact with the spring tabs 214, thus allowing for a change in state(second state) of the RF tag 211. In this second state, the RF tag 211may broadcast (if active) or present (if passive, read by an externalreader 212) a second state to include a used status. Alternatively theRF tag 211 may be deformed or altered in such a way upon use of theinjection device that, upon interrogation, the RF tag 211 presents a‘used’ signature. For instance, if the RF tag consists of two coilsjoined by a conductor, the initial signature of the tag 211 would be the‘dual coil’ signature. Once the tag 211 has been used, if the conductorjoining the two coils is broken, then the two independent coils producea different signature.

Location of the RF tab or chip outside of the injection device may bedesired for regulatory and/or disposability reasons. For example, the RFtag or chip 211 also may be associated with the transfer device or withanother part of the system, such as for example, safety sleeve or pulltab 100 (see FIG. 83), to activate the tag or chip at a selected pointor points in the operation of the transfer device and/or injectiondevice. An active RF tag or chip could, for example, be located on thesafety sleeve and configured so that removal of the safety sleeve tostart the injection process closes a contact between a long shelf-lifebattery and the tag or chip transmitter.

In other words, the RF chip or tag may have two states, a standby or offstate and an active, or transmitting, state. The state may be changed bymaking or breaking a contact. Making contact could be achieved, forexample, by configuring the contacts on safety release or pull tab 100so that they remain in a spaced apart relation when the pull tab is inposition on the injection device, and so that they come together tocontact one another when the pull tab is removed from the injectiondevice to start the injection. Further, different actions associatedwith the use of the transfer and/or injection device could be employedto make or break contact. For example, a previously inactive RF tag orchip could be activated by closing a contact between a battery and thechip or tag transmitter when one action is taken, such as when a vial isinserted into the transfer device, and deactivated by another action,such as by breaking such contact after use of injection device.

Referring to FIGS. 96-98, for further example, the transfer device 215may include an RF tag 211 to track the usage of the transfer package215. For example, the RF tag 211 may broadcast to an external reader 212(if active) or present (if passive, read by an external reader 212)information such as—the transfer package 215 has been opened, the vial216 has been inserted, the transfer package 215 has been actuated,and/or the injector 210 has been removed from the transfer package 215.Referring to FIGS. 97-98, in another embodiment, the transfer device 215may include provisions for reading an RF tag 211 within the injectiondevice 206. For instance, in the existing transfer packages 215, theactive RF transmission could occur once the vial/syringe/cartridge 216is inserted into the transfer device 215, or once the locking blade 217is retracted, or once the injector 210 is removed. An advantage ofmounting the active transmitter 220 in the transfer device 215 is thereis more room for mounting and/or power supply, and the transmitter 220does not need to reside on the injector 210.

The RF tag or chip 211 may transmit or communicate data associated withthe transfer or injection device—in addition to use information. Forexample, the tag or chip may be configured, with memory storagecapacity, to transmit the type of injection device, lot number, fluidquantity administered, drug identification and other relevantinformation. FIG. 99 diagrammatically illustrates one system that may beemployed with the present subject matter. As shown there, the RF tag orchip 250 may be of the active type, and when activated activelytransmits the pertinent information to a local Patient Module 252located within the vicinity of the patient and injection device. Forexample, the Patient Module could be a wall-mounted or desktop devicelocated in the patient's home for receiving the monitoring informationtransmitted by the RF tag or chip associated with the injection deviceand/or transfer device. The Patient Module could also be a cellulartelephone or the like.

The Patient Module could include a memory that maintains data such aspatient identification and related information. The Patient Module, inturn, communicates in an appropriate manner, such WIFI, cellularcommunication, telephone, hard wire link or other, with a Data Manager254, which could be any appropriate data network or Cloud storagearrangement for receiving and/or storing data received from the PatientModule indicating injection device status and/or usage in associationwith the particular identifying patient information. The Data Managerwould be accessible by medical personnel responsible for the monitoringof the patient's use of the injection device and patient compliance withany prescribed injection regimen. The Data Manager could also beconfigured to automatically relay patient compliance information to theappropriate medical personnel, such as a particular physician or clinic256.

Other aspects of a compliance monitoring apparatus, system and methodand use with an injection device such as described herein are shown inFIGS. 105-109. As illustrated there, the system may include a wireless,e.g., Bluetooth, source, such as a battery powered sending unit such asa microchip, indicated at 262 in FIGS. 107 and 108. The sending unit maybe mounted in any suitable location, and can be associated with orattached to a part of the injection device (an/or transfer device) in amanner so that it can be detached from the injection device or transferdevice at the time of disposal—allowing most of the injection device ortransfer device structure to be recycled, as electronic circuitry andelectronic chips are typically not similarly recyclable.

In addition, with reference to FIG. 108, a contactor ring 264 isprovided in the top of the of the injection device housing and isprevented from making contact with sensing leads 266 (which are attachedto the injection device button) when the safety strip 100 is installed(as illustrated in FIG. 83). When the safety strip 100 is removed, thecontactor ring 264 of the housing makes contact with the sensing leads266 of the button. Different sequences of the injection process may thenbe tracked based on the connection status between the contactor ring andthe sensing leads (i.e. position of the contactor ring 264 with respectto the sensing leads 266). Infrared sensors 268 may also be embedded inthe injection device to optically track delivery progress, such as by,for example, monitoring of the position of, or amount of injectablefluid in, expandable member of the injection device.

The present subject matter has been described in terms of specificembodiments for purposes of illustration only, and not limitation. It isto be understood that the scope of the subject matter is not limited toonly the illustrated embodiments or equivalents thereof but has broaderapplication in embodiments of varying configuration and use some ofwhich may be readily apparent upon reading this description and othersonly after some study and/or development.

What is claimed is:
 1. A medication injection device comprising: ahousing having a skin-facing surface configured to contact a user'sskin; a skin displacement structure extending from and surrounded by theskin-facing surface, said skin displacement structure including aninjection needle aperture positioned therein and defining an injectionneedle aperture opening; an injection needle that slidably extends outof the injection needle aperture opening and beyond the skindisplacement structure, wherein the injection needle is movable from aninitial retracted position to an injection position extending to aselected subcutaneous depth for injection and back to a final retractedposition after an injection is complete; said injection needle aperturecontaining a septum that is positioned within the skin displacementstructure, where the septum contacts and guides the injection needle asit slidably extends; the skin displacement structure serving to compresstissue around the injection needle aperture opening and thereby creatinga tissue pressure zone around the injection needle aperture openinghaving higher pressure than in tissue outwardly of the tissue pressurezone, the medication injection device being configured to maintain thetissue pressure zone after the needle returns to the final retractedposition.
 2. The medication injection device of claim 1 wherein theinjection needle is extendable through the injection needle aperturesufficiently to extend not more than about 5 mm into tissue when theskin-facing surface is placed in contact with the user's skin.
 3. Themedication injection device of claim 2 in which the injection needleextends to a subcutaneous depth of about 5 mm and generates a medicationbolus depth of about 0.4 cm-about 0.45 cm.
 4. The medication injectiondevice of claim 1 wherein the injection needle is extendable through theinjection needle aperture sufficiently to extend a selected subcutaneousdistance into tissue, the selected subcutaneous distance providingsubstantially similar medication bolus depth as an injection needleextending substantially twice the selected depth in an absence of skindisplacement.
 5. The medication injection device of claim 1 wherein theskin displacement structure is configured to form an extension contactarea within a user's skin, said extension contact area having agenerally concave profile containing a point of needle insertion.
 6. Themedication injection device of claim 5 wherein the extension contactarea extends radially outwards from the point of needle insertion. 7.The medication injection device of claim 6 wherein the point of needleinsertion is centrally located within the concave profile of theextension contact area.
 8. The mediation injection device of claim 1wherein the skin displacement structure includes a tip having agenerally planar skin contact surface including the injection needleaperture opening.
 9. The medication injection device of claim 1 whereinthe skin displacement structure compresses tissue surrounding andextending radially outwards from the injection needle aperture openingwhen the skin-facing surface is in contact with the user's skin.
 10. Themedication injection device of claim 1 wherein the skin-facing surfaceincludes adhesive that is configured to secure the medication injectiondevice to the user's skin.